Acute Hepatic Failure
Frederick J. Suchy, Amy G. Feldman
Acute liver failure is a clinical syndrome resulting from massive necrosis of hepatocytes or from severe functional impairment of hepatocytes. The synthetic, excretory, and detoxifying functions of the liver are all severely impaired. In adults, hepatic encephalopathy has been an essential diagnostic feature. However, in pediatrics, this narrow definition may be problematic, as early hepatic encephalopathy can be difficult to detect in infants and children, and some children in acute liver failure may not develop encephalopathy. The accepted definition in children includes biochemical evidence of acute liver injury (usually <8 wk duration); no evidence of chronic liver disease; and hepatic-based coagulopathy defined as a prothrombin time (PT) >15 sec or international normalized ratio (INR) >1.5 not corrected by vitamin K in the presence of clinical hepatic encephalopathy, or a PT >20 sec or INR >2 regardless of the presence of clinical hepatic encephalopathy.
Liver failure in the perinatal period can be associated with prenatal liver injury and even cirrhosis. Examples include gestational alloimmune liver disease (GALD), tyrosinemia, familial hemophagocytic lymphohistiocytosis (HLH), and some cases of congenital viral (herpes simplex virus [HSV]) infection. Liver disease may be noticed at birth or after several days of apparent well-being. Fulminant Wilson disease and fulminant autoimmune hepatitis also occurs in older children who were previously asymptomatic but, by definition, have preexisting liver disease. Other forms of acute-on-chronic liver failure can occur when a patient with an underlying liver disease such as biliary atresia develops hepatic decompensation after viral or drug-induced hepatic injury. In some cases of liver failure, particularly in the idiopathic form of acute hepatic failure, the onset of encephalopathy occurs later, from 8 to 28 wk after the onset of jaundice.
Etiology
Infection
Acute hepatic failure can be a complication of viral hepatitis (A, B, D, and rarely E), Epstein-Barr virus, herpes simplex virus, adenovirus, enterovirus, influenza A, cytomegalovirus, parvovirus B19, human herpesvirus-6, varicella zoster infection, parechovirus, and other respiratory illnesses. An unusually high rate 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 are 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 E virus is an uncommon cause of fulminant hepatic failure in the United States, but can occur in pregnant women, in whom mortality rates rise dramatically to up to 25%. Patients with chronic hepatitis C are at risk if they have superinfection with hepatitis A virus.
Autoimmune Hepatitis
Acute hepatic failure is caused by autoimmune hepatitis in approximately 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 immunoglobulin G level. If a biopsy can be performed, liver histology often demonstrates interface hepatitis and a plasma cell infiltrate.
Metabolic Diseases
Metabolic disorders associated with hepatic failure include Wilson disease, acute fatty liver of pregnancy, galactosemia, hereditary tyrosinemia, hereditary fructose intolerance, defects in β-oxidation of fatty acids, and deficiencies of mitochondrial electron transport, in particular mitochondrial DNA depletion disorders. Patients with Wilson disease who present in acute liver failure often have high bilirubin levels, low alkaline phosphatase levels, low uric acid levels, aspartate aminotransferase levels that are higher than alanine aminotransferase levels, and a Coombs-negative hemolytic anemia.
Neoplasm
Acute liver failure can occur with malignancies including leukemia, lymphoma, and familial HLH . Acute liver failure is a common feature of 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 cells and cytotoxic T-lymphocyte cells with uncontrolled hemophagocytosis and cytokine overproduction is characteristic for genetic and acquired forms of HLH. Patients with HLH present with a combination of fever, splenomegaly, cytopenias, high triglyceride levels, very high ferritin levels, low natural killer cell activity, high soluble CD25 levels; they may also have hemophagocytosis on bone marrow or liver biopsy (see Chapter 534 ).
Gestational Alloimmune Liver Disease
GALD is the most common cause of acute liver failure in the neonate. In this alloimmune process, maternal immunoglobulin (Ig) G antibodies bind to fetal liver antigens and activate the terminal complement cascade resulting in hepatocyte injury and death. Infants with GALD present with low/normal aminotransferases that are out of proportion to their degree of liver failure. They may have significant hypoglycemia, jaundice, coagulopathy, and hypoalbuminemia. Alpha fetoprotein levels are typically high as are serum ferritin levels.
Drug-Induced Liver Injury
Various hepatotoxic drugs and chemicals can also cause drug-induced liver injury and acute hepatic failure. Predictable liver injury can occur after exposure to carbon tetrachloride, Amanita phalloides mushrooms or after acetaminophen overdose. Acetaminophen is the most common identifiable 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, ecstasy, or sodium valproate. Herbal and weight loss supplements are additional causes of hepatic failure (see Chapter 390 ).
Vascular
Ischemia and hypoxia resulting from hepatic vascular occlusion, severe heart failure, cyanotic congenital heart disease, or circulatory shock can produce liver failure.
Idiopathic Acute Liver Failure
Idiopathic acute liver failure accounts for 40–50% of acute hepatic failure 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, excessive immune activation, and undiagnosed genetic or metabolic disorders. There is increasing recognition of some children presenting with indeterminate acute hepatitis or acute liver failure who have evidence of immune activation including markedly elevated sIL-2R levels but never fulfilling diagnostic criteria for HLH.
Recurrent, acute liver failure has been reported with onset in infancy due to mutations of the neuroblastoma amplified sequence gene (NBAS) . Episodes are usually precipitated by fever and characterized by bouts of vomiting and lethargy. Massively elevated aminotransferase levels and coagulopathy are present. Microvesicular steatosis is prominent on liver biopsy. Most patients recovered with restoration of normal liver function after control of fever and maintenance of energy balance with the infusion of intravenous glucose. The function of NBAS protein remains uncertain but it appears to be involved in retrograde transport between the endoplasmic reticulum and Golgi apparatus.
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 acute hepatic failure are poorly understood. It is unknown why only approximately 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. 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; acute 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.
Clinical Manifestations
Acute hepatic failure can be the presenting feature of liver disease or it can complicate previously known liver disease (acute-on-chronic liver failure). A history of developmental delay and/or neuromuscular dysfunction can indicate an underlying mitochondrial or β-oxidation defect. A child with acute 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 391.1 ). The pathogenesis of hepatic encephalopathy is likely related to increased serum levels of ammonia, false neurotransmitters, amines, increased γ-aminobutyric acid receptor activity, or increased circulating levels of endogenous benzodiazepine-like compounds. Decreased hepatic clearance of these substances can produce marked central nervous system dysfunction. The mechanisms responsible for cerebral edema and intracranial hypertension in acute liver failure (ALF) suggest both cytotoxic and vasogenic injury. There is increasing evidence for an inflammatory response (synthesis and release of inflammatory factors from activated microglia and endothelial cells) which acts in synergy with hyperammonemia to cause severe astrocyte swelling/brain edema.
Table 391.1
Stages of Hepatic Encephalopathy
| STAGES | ||||
|---|---|---|---|---|
| I | II | III | IV | |
| Symptoms | Periods of lethargy, euphoria; reversal of day-night sleeping; may be alert | Drowsiness, inappropriate behavior, agitation, wide mood swings, disorientation | Stupor but arousable; confused, incoherent speech |
Coma: IVa responds to noxious stimuli; IVb no response |
| Signs | Trouble drawing figures, performing mental tasks | Asterixis, fetor hepaticus, incontinence | Asterixis, hyperreflexia, extensor reflexes, rigidity | Areflexia, no asterixis, flaccidity |
| Electroencephalogram | Normal | Generalized slowing, q waves | Markedly abnormal triphasic waves | Markedly abnormal bilateral slowing, d waves, electrocortical silence |
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 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 also develop.
Treatment
Specific therapies for identifiable causes of acute liver failure include N -acetylcysteine (acetaminophen), acyclovir (herpes simplex virus), penicillin (Amanita mushrooms), nucleos(t)ide analogs such as entecavir (hepatitis B virus [HBV]), and prednisone (autoimmune hepatitis). Immunosuppression with corticosteroids should also be considered in children with the indeterminate form of fulminant hepatic failure with immune activation to avoid progression to liver transplantation or death. However, controlled trials have shown a worse outcome in patients treated with corticosteroids in patients without an immune basis for liver injury. Treatment of GALD involves a combination of double-volume exchange transfusion to remove existing reactive antibody followed immediately by administration of high-dose intravenous immunoglobulin (IVIG) (1 g/kg) to block antibody induced complement activation. Management of other types of acute 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; 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. Fresh-frozen plasma, cryoprecipitate, platelets, activated factor VII, or prothrombin complex concentrates can be used to treat clinically significant bleeding or can be given if an invasive procedure such as placement of a central line or an intracranial monitor needs to be performed. Plasmapheresis can permit temporary correction of the bleeding diathesis without resulting in volume overload. Continuous hemofiltration is useful for managing fluid overload, acute renal failure, and hyperammonemia.
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, Staphylococcus 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. If encephalopathy or hyperammonemia develops, lactulose or rifaximin can be administered. N -acetylcysteine is not 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.
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 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. Orthotopic liver transplantation 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 transplantation.
Prognosis
Children with acute hepatic failure fare better than adults. Improved survival can be attributed to careful intensive care and if necessary liver transplantation. In the largest prospective study from the Pediatric Acute Liver Failure Study Group, 709 children were assessed at 21 days: 50.3% of patients survived with supportive care alone, 36.2% survived after liver transplantation, and 13.4% died. A scoring system based on peak values of total serum bilirubin, PT, and plasma ammonia concentration predicted transplant-free survival. Prognosis varies considerably with the cause of liver failure and stage of hepatic encephalopathy. Survival rates with supportive care may be as high as 90% in acetaminophen overdose and with fulminant hepatitis A. By contrast, spontaneous recovery can be expected in only approximately 40% of patients with liver failure caused by the idiopathic (indeterminate) form of acute liver failure or an acute onset of Wilson disease. Prognosis is also poor for spontaneous recovery in patients with mitochondrial deficits, hemophagocytic syndromes, herpes simplex disease, and idiosyncratic drug reactions. In patients who progress to stage IV coma (see Table 391.1 ), the prognosis is extremely poor. Brain stem 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, PT >90 sec, low factor V levels, and the need for dialysis before transplantation are associated with increased mortality. Pretransplantation serum bilirubin concentration or the height of hepatic enzymes is not predictive of posttransplantation survival. A plasma ammonia concentration >200 µmol/L is associated with a 5-fold increased risk of death. Children with acute hepatic failure are more likely to die while on the waiting list compared to children with other liver transplant requiring diagnoses. Owing to the severity of their illness, the 6 mo post–liver transplantation survival of approximately 75% for acute liver failure 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 approximately 10% of children with the idiopathic form of fulminant hepatic failure and is often fatal without bone marrow transplantation. Long-term survivors demonstrate average IQ and visual spatial ability but greater than expected impairments in motor skills, attention, executive function, and health-related quality of life.