Etiology

Fulminant hepatic failure can be a complication of viral hepatitis (A, B, D, E). An unusually high risk of fulminant hepatic failure occurs in young people who have combined infections with the hepatitis B virus (HBV) and hepatitis D. Mutations in the precore and/or promoter region of HBV DNA have been associated with fulminant and severe hepatitis. HBV is also responsible for some cases of fulminant liver failure in the absence of serologic markers of HBV infection but with HBV DNA found in the liver. Hepatitis C and E viruses are uncommon causes of fulminant hepatic failure in the United States. Patients with chronic HCV are at risk if they have superinfection with HAV. Epstein-Barr virus, herpes simplex virus (HSV), adenovirus, enteroviruses, cytomegalovirus, parvovirus B19, human herpesvirus-6, and varicella-zoster infections can also produce fulminant hepatitis in children.

Fulminant hepatic failure can also be caused by autoimmune hepatitis in ~5% of cases. Patients have a positive autoimmune marker (e.g., antinuclear antibody, anti–smooth muscle antibody, liver-kidney microsomal antibody, or soluble liver antigen) and possibly an elevated serum IgG level. Liver histology, if a biopsy can be safely done, might support the diagnosis.

Acute liver failure is a common feature of hemophagocytic lymphohistocytosis (HLH) caused by several gene defects, infections by mostly viruses of the herpes group, and a variety of other conditions including organ transplantation and malignancies. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) with uncontrolled hemophagocytosis and cytokine overproduction is characteristic for genetic and acquired forms of HLH. Biochemical markers include elevated ferritin and triglycerides and low fibrinogen.

An idiopathic form of fulminant hepatic failure accounts for 40-50% of cases in children. The disease occurs sporadically and usually without the risk factors for common causes of viral hepatitis. It is likely that the etiology of these cases is heterogeneous, including unidentified or variant viruses and undiagnosed metabolic disorders.

Various hepatotoxic drugs and chemicals can also cause fulminant hepatic failure. Predictable liver injury can occur after exposure to carbon tetrachloride or Amanita phalloides mushroom or after acetaminophen overdose. Acetaminophen is the most common etiology of acute hepatic failure in children and adolescents in the United States and England. In addition to the acute intentional ingestion of a massive dose, a therapeutic misadventure leading to severe liver injury can also occur in ill children given doses of acetaminophen exceeding weight-based recommendations for many days. Such patients can have reduced stores of glutathione after a prolonged illness and a period of poor nutrition. Idiosyncratic damage can follow the use of drugs such as halothane, isoniazid, or sodium valproate. Herbal supplements are additional causes of hepatic failure (see Table 355-2).

Ischemia and hypoxia resulting from hepatic vascular occlusion, severe heart failure, cyanotic congenital heart disease, or circulatory shock can produce liver failure. Metabolic disorders associated with hepatic failure include Wilson disease, acute fatty liver of pregnancy, galactosemia, hereditary tyrosinemia, hereditary fructose intolerance, neonatal iron storage disease, defects in β-oxidation of fatty acids, and deficiencies of mitochondrial electron transport.

Pathology

Liver biopsy usually reveals patchy or confluent massive necrosis of hepatocytes. Multilobular or bridging necrosis can be associated with collapse of the reticulin framework of the liver. There may be little or no regeneration of hepatocytes. A zonal pattern of necrosis may be observed with certain insults. (Centrilobular damage is associated with acetaminophen hepatotoxicity or with circulatory shock.) Evidence of severe hepatocyte dysfunction rather than cell necrosis is occasionally the predominant histologic finding (microvesicular fatty infiltrate of hepatocytes is observed in Reye syndrome, β-oxidation defects, and tetracycline toxicity).

Pathogenesis

The mechanisms that lead to fulminant hepatic failure are poorly understood. It is unknown why only about 1-2% of patients with viral hepatitis experience liver failure. Massive destruction of hepatocytes might represent both a direct cytotoxic effect of the virus and an immune response to the viral antigens. One third to one half of patients with HBV-induced liver failure become negative for serum hepatitis B surface antigen within a few days of presentation and often have no detectable HBV antigen or HBV DNA in serum. These findings suggest a hyperimmune response to the virus that underlies the massive liver necrosis. Formation of hepatotoxic metabolites that bind covalently to macromolecular cell constituents is involved in the liver injury produced by drugs such as acetaminophen and isoniazid; fulminant hepatic failure can follow depletion of intracellular substrates involved in detoxification, particularly glutathione. Whatever the initial cause of hepatocyte injury, various factors can contribute to the pathogenesis of liver failure, including impaired hepatocyte regeneration, altered parenchymal perfusion, endotoxemia, and decreased hepatic reticuloendothelial function.

The pathogenesis of hepatic encephalopathy can relate to increased serum levels of ammonia, false neurotransmitters, amines, increased γ-aminobutyric acid (GABA) receptor activity, or increased circulating levels of endogenous benzodiazepine-like compounds. Decreased hepatic clearance of these substances can produce marked central nervous system dysfunction.

Clinical Manifestations

Fulminant hepatic failure can be the presenting feature of liver disease or it can complicate previously known liver disease. A history of developmental delay and/or neuromuscular dysfunction can indicate an underlying mitochondrial or β-oxidation defect. A child with fulminant hepatic failure has usually been previously healthy and most often has no risk factors for liver disease such as exposure to toxins or blood products. Progressive jaundice, fetor hepaticus, fever, anorexia, vomiting, and abdominal pain are common. A rapid decrease in liver size without clinical improvement is an ominous sign. A hemorrhagic diathesis and ascites can develop.

Patients should be closely observed for hepatic encephalopathy, which is initially characterized by minor disturbances of consciousness or motor function. Irritability, poor feeding, and a change in sleep rhythm may be the only findings in infants; asterixis may be demonstrable in older children. Patients are often somnolent, confused, or combative on arousal and can eventually become responsive only to painful stimuli. Patients can rapidly progress to deeper stages of coma in which extensor responses and decerebrate and decorticate posturing appear. Respirations are usually increased early, but respiratory failure can occur in stage IV coma (Table 356-1).

Laboratory Findings

Serum direct and indirect bilirubin levels and serum aminotransferase activities may be markedly elevated. Serum aminotransferase activities do not correlate well with the severity of the illness and can actually decrease as a patient deteriorates. The blood ammonia concentration is usually increased, but hepatic coma can occur in patients with a normal blood ammonia level. PT and the INR are prolonged and often do not improve after parenteral administration of vitamin K. Hypoglycemia can occur, particularly in infants. Hypokalemia, hyponatremia, metabolic acidosis, or respiratory alkalosis can develop.

Treatment

Specific therapies for identifiable causes of acute liver failure include N-acetylcysteine (acetaminophen), acyclovir (HSV), penicillin (Amanita mushrooms), lamivudine (HBV), prednisone (autoimmune hepatitis), and pleconaril (enteroviruses). Management of other types of fulminant hepatic failure is supportive. No therapy is known to reverse hepatocyte injury or to promote hepatic regeneration.

An infant or child with acute hepatic failure should be cared for in an institution able to perform a liver transplantation if necessary and managed in an intensive care unit with continuous monitoring of vital functions. Endotracheal intubation may be required to prevent aspiration, to reduce cerebral edema by hyperventilation, and to facilitate pulmonary toilet. Mechanical ventilation and supplemental oxygen are often necessary in advanced coma. Sedatives should be avoided unless needed in the intubated patient because these agents can aggravate or precipitate encephalopathy. Opiates may be better tolerated than benzodiazepines. Prophylactic use of proton pump inhibitors should be considered because of the high risk of gastrointestinal bleeding.

Hypovolemia should be avoided and treated with cautious infusions of isotonic fluids and blood products. Renal dysfunction can result from dehydration, acute tubular necrosis, or functional renal failure (hepatorenal syndrome). Electrolyte and glucose solutions should be administered intravenously to maintain urine output, to correct or prevent hypoglycemia, and to maintain normal serum potassium concentrations. Hyponatremia is common and should be avoided, but it is usually dilutional and not a result of sodium depletion. Parenteral supplementation with calcium, phosphorus, and magnesium may be required. Hypophosphatemia, probably a reflection of liver regeneration, and early phosphorus administration are associated with a better prognosis in acute liver failure, whereas hyperphosphatemia predicts a failure of spontaneous recovery.

Coagulopathy should be treated with parenteral administration of vitamin K and can require infusion of fresh frozen plasma, cryoprecipitate, and platelets to treat clinically significant bleeding; disseminated intravascular coagulation can also occur. Plasmapheresis can permit temporary correction of the bleeding diathesis without resulting in volume overload. Recombinant factor VIIa has been used for transient correction of coagulopathy refractory to fresh frozen plasma infusions and can facilitate the performance of invasive procedures such as placement of a central line or an intracranial pressure monitor. Continuous hemofiltration is useful for managing fluid overload and acute renal failure.

Patients should be monitored closely for infection, including sepsis, pneumonia, peritonitis, and urinary tract infections. At least 50% of patients experience serious infection. Gram-positive organisms (Staphylococcus aureus, S. epidermidis) are the most common pathogens, but gram-negative and fungal infections are also observed.

Gastrointestinal hemorrhage, infection, constipation, sedatives, electrolyte imbalance, and hypovolemia can precipitate encephalopathy and should be identified and corrected. Protein intake should be initially restricted or eliminated, depending on the degree of encephalopathy. The gut should be purged with several enemas. Lactulose should be given every 2-4 hr orally or by nasogastric tube in doses (10-50 mL) sufficient to cause diarrhea. The dose is then adjusted to produce several acidic, loose bowel movements daily. Lactulose syrup diluted with 1-3 volumes of water can also be given as a retention enema every 6 hr. Lactulose, a nonabsorbable disaccharide, is metabolized to organic acids by colonic bacteria; it probably lowers blood ammonia levels through decreasing microbial ammonia production and through trapping of ammonia in acidic intestinal contents. Oral or rectal administration of a nonabsorbable antibiotic such as rifaximin or neomycin can reduce enteric bacteria responsible for ammonia production. Oral antibiotics may be more effective than lactulose in lowering serum ammonia levels. Flumazenil, a benzodiazepine antagonist, can temporally reverse early hepatic encephalopathy. N-Acetylcysteine has also been effective in improving the outcome of patients with acute liver failure not associated with acetaminophen.

Cerebral edema is an extremely serious complication of hepatic encephalopathy that responds poorly to measures such as corticosteroid administration and osmotic diuresis. Monitoring intracranial pressure can be useful in preventing severe cerebral edema, in maintaining cerebral perfusion pressure, and in establishing the suitability of a patient for liver transplantation. Controlled trials have shown a worsened outcome of fulminant hepatic failure in patients treated with corticosteroids.

Temporary liver support continues to be evaluated as a bridge for the patient with liver failure to liver transplantation or regeneration. Nonbiologic systems, essentially a form of liver dialysis with an albumin-containing dialysate, and biologic liver support devices that involve perfusion of the patient’s blood through a cartridge containing liver cell lines or porcine hepatocytes can remove some toxins, improve serum biochemical abnormalities, and, in some cases, improve neurologic function, but there has been little evidence of improved survival, and few children have been treated.

Orthotopic liver transplantation (OLT) can be lifesaving in patients who reach advanced stages (III, IV) of hepatic coma. Reduced-size allografts and living donor transplantation have been important advances in the treatment of infants with hepatic failure. Partial auxiliary orthotopic or heterotopic liver transplantation is successful in a small number of children, and in some cases it has allowed regeneration of the native liver and eventual withdrawal of immunosuppression. OLT should not be done in patients with liver failure and neuromuscular dysfunction secondary to a mitochondrial disorder because progressive neurologic deterioration is likely to continue after transplant.

Prognosis

Children with hepatic failure might fare somewhat better than adults, but overall mortality with supportive care alone exceeds 70%. The prognosis varies considerably with the cause of liver failure and stage of hepatic encephalopathy. With intensive medical support, survival rates of 50-60% occur with hepatic failure, complicating acetaminophen overdose (may be as high as 90%) and with fulminant HAV or HBV infection. By contrast, spontaneous recovery can be expected in only 10-20% of patients with liver failure caused by the idiopathic form of acute liver failure or an acute onset of Wilson disease. In patients who progress to stage IV coma (see Table 356-1), the prognosis is extremely poor. Brainstem herniation is the most common cause of death. Major complications such as sepsis, severe hemorrhage, or renal failure increase the mortality. The prognosis is particularly poor in patients with liver necrosis and multiorgan failure. Age <1 yr, stage 4 encephalopathy, an INR >4, and the need for dialysis before transplantation have been associated with increased mortality. Pretransplant serum bilirubin concentration or the height of hepatic enzymes is not predictive of post-transplant survival. Children with acute hepatic failure are more likely to die while on the waiting list compared to children with other diagnoses. Owing to the severity of their illness, the 6 mo post–liver transplantation survival of ~75% is significantly lower than the 90% achieved in children with chronic liver disease. Patients who recover from fulminant hepatic failure with only supportive care do not usually develop cirrhosis or chronic liver disease. Aplastic anemia occurs in ~10% of children with the idiopathic form of fulminant hepatic failure and is often fatal.