Fulminant Hepatic Failure and Encephalopathy
Fulminant hepatic failure (FHF), acute hepatic failure, and fulminant hepatitis all refer to acute severe impairment of liver function accompanied by coagulopathy, advanced stages encephalopathy, and coma in patients who have had liver disease for less than 8 weeks. FHF, in most instances, is complicated by multiorgan failure and cerebral edema, lasts 1 to 4 weeks, and ends fatally in 60% to 95% of patients. FHF is a rare condition with an incidence of 2,000 cases per year in the United States.
In a subgroup of patients, the duration of illness before the onset of encephalopathy is more prolonged (subacute FHF) but as in FHF, there is no evidence of previous liver disease. In patients with late-onset hepatic failure, hepatic encephalopathy and other evidence of hepatic decompensation appear between 8 and 24 weeks after the first symptoms. Patients with late-onset disease are significantly older than those who have FHF; median ages of onset are 44.5 years and 25.5 years, respectively.
Liver transplantation may be the ultimate solution in FHF.
New terminology has been introduced and is based on the interval from the onset of jaundice to the development of encephalopathy.
Hyperacute liver failure, with an interval of <7 days
Acute liver failure, with an interval of 8-28 days
Subacute liver failure, with an interval of 4-12 weeks.
I. ETIOLOGY.
Table 17-1 outlines the numerous causes of FHF.
A. Hepatitis.
FHF is most commonly seen with viral and toxic hepatitis. In fact, viruses are implicated in 75% of instances.
1.
FHF is most commonly seen with hepatitis B virus (HBV) infection; 1% of patients acutely infected with HBV may develop the syndrome. Thirty to forty percent of these patients may be infected concomitantly with the hepatitis delta virus (HDV). Infection with hepatitis A virus (HAV), and rarely hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and parvovirus B19 also may lead to FHF. Enterically transmitted hepatitis E virus may cause FHF in pregnant women, especially in the third trimester.
2. Acute toxic hepatitis
may result from an idiosyncratic hypersensitivity reaction to a drug (e.g., halothane, isoniazid, rifampin, alpha-methyldopa) or from substances that are intrinsically toxic to the liver (e.g., acetaminophen, hydrocarbons, white phosphorus, some poisonous mushrooms).
3.
These toxic agents and viral infections cause panlobular hepatic necrosis resulting in FHF.
B. Hepatic ischemia
resulting from severe hypoxemia, hypotension, cardiac failure, or acute Budd-Chiari syndrome may cause extensive centrilobular hepatic necrosis and FHF.
C. Wilson’s disease
may present as FHF accompanied by acute intravascular hemolysis.
D.
FHF may result from a group of disorders characterized by acute extensive infiltration of hepatocytes with microdroplets of fat and minimal hepatocellular necrosis. These disorders include Reye’s syndrome, tetracycline induced fatty liver, fatty liver of pregnancy, fatty liver after jejunoileal bypass surgery, and acute alcoholic hepatitis. Dideoxyinosine (DDI) used in the treatment of acquired immunodeficiency syndrome (AIDS) also may cause this condition.
TABLE 17-1 Causes of Fulminant Hepatic Failure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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E.
Rarely, FHF may develop in patients who have one of the hematolymphoid malignancies, such as malignant histiocytosis, Burkitt’s lymphoma, the acute phase of chronic myelogenous leukemia, acute monoblastic leukemia, and Hodgkin’s and non-Hodgkin’s lymphomas. Massive infiltration of hepatic parenchyma with malignant cells results in infarction and necrosis, leading to FHF.
II. DIAGNOSIS.
Serum aminotransferase (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) and bilirubin levels may provide useful clues regarding the cause of FHF. In toxic or viral FHF, the serum aminotransferases are significantly elevated due to injury to the hepatocytes. In instances of acute fatty infiltration and mitochondrial damage, aminotransferases are only moderately elevated.
The presence in serum of IgM antibody to HAV supports the diagnosis of acute hepatitis A. The presence of hepatitis B surface antigen (HBsAg) or IgM antibody to hepatitis B core particle (HBcAb) or both and HBV-DNA in a patient with FHF favors hepatitis B as the etiologic agent. IgM antibody to the delta virus can be detected by serologic study only in patients carrying HBsAg. Antibody to hepatitis C may help in establishing the diagnosis of hepatitis C but may not be detectable in the acute phase
of the disease. A mutant form of hepatitis B and rarely hepatitis C is implicated in most instances of late-onset hepatic failure. Determination of viral DNA or RNA titers of hepatitis B and C viruses by polymerase chain reaction respectively may give information that is more accurate in the cases of viral hepatitis B or C.
of the disease. A mutant form of hepatitis B and rarely hepatitis C is implicated in most instances of late-onset hepatic failure. Determination of viral DNA or RNA titers of hepatitis B and C viruses by polymerase chain reaction respectively may give information that is more accurate in the cases of viral hepatitis B or C.
Liver biopsy may be helpful in establishing a diagnosis but may be difficult to perform because of the severe coagulopathy, which is not correctable with replacement of clotting factors.
III. PROGNOSIS.
Survival from FHF depends on the ability of the liver to regenerate with restitution of the normal hepatic function. Prothrombin time greater than 100 seconds, regardless of the stage of encephalopathy or the presence of any three of the following findings, indicates a poor prognosis in FHF caused by viral hepatitis or drug toxicity excluding acetaminophen toxicity:
Arterial pH <7.3
Age <10 or >40 years
Jaundice >7 days before the onset of encephalopathy
Prothrombin time >50 seconds
Serum bilirubin >18 mg/dL
Prognosis in FHF depends on the age of the patient, cause of the acute liver failure, clinical course, occurrence of secondary complications, and duration and severity of the coma.
A. Causes of death
in FHF are neurologic complications (67%), gastrointestinal hemorrhage (13%), bacterial and/or fungal infection and sepsis (13%), hemodynamic complications (8%), and progressive respiratory and renal failure.
IV. CLINICAL SYNDROME
A. The encephalopathy
of FHF may begin with mild confusion, irrational behavior, euphoria, or psychosis. It is usually associated with a widely fluctuating but progressive deterioration of the mental state. Coma may develop rapidly within several days of onset of symptoms.
1. The pathogenesis
of hepatic encephalopathy (HE) is unknown, but there are several theories. HE is a potentially reversible metabolic disorder of the brain in the milieu of hepatic failure.
a. “Neurotoxic” substances. The ability of the liver to remove toxic substances from the circulation is important in the maintenance of normal brain function. In liver failure, it is assumed that neurotoxic substances normally extracted from portal venous blood and metabolized in the liver gain access to the systemic circulation and reach the brain parenchyma through a more permeable blood-brain barrier. These substances may be directly toxic to the neurons or may modulate neuronal function by causing changes in the metabolism of neurotransmitters or the functional status of the neurotransmitter receptors. The toxic substances most commonly implicated in hepatic failure are ammonia (NH3), γ-aminobutyric acid (GABA), endogenous “benzodiazepines and opioids,” mercaptans, and fatty acids.
b. “False neurotransmitters.”
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