Fulminant Hepatic Failure

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Chapter 356 Fulminant Hepatic Failure

Frederick J. Suchy

Fulminant hepatic failure (acute liver failure) is a clinical syndrome resulting from massive necrosis of hepatocytes or from severe functional impairment of hepatocytes. Synthetic, excretory, and detoxifying functions of the liver are all severely impaired. In adults, hepatic encephalopathy has been an essential diagnostic feature. This narrow definition may be problematic because early hepatic encephalopathy can be difficult to detect in infants and children. The currently 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 neonatal iron storage (hemochromatosis) disease, tyrosinemia, and some cases of congenital viral infection. Liver disease may be noticed at birth or after several days of apparent well-being. Fulminant Wilson disease also occurs in older children who were previously asymptomatic but, by definition, have pre-existing liver disease. 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

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

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