Hepatic Failure: Complications and TherapyAcute Liver Failure Including Acetaminophen Overdose
Section snippets
Etiology in the United States
The low annual incidence of ALF in the United States, estimated at 2800 cases per annum, makes it difficult to collect reliable data on the causes, risk factors, and outcomes of this clinical syndrome [2], [4]. This low annual incidence also can lead to referral bias, selection bias, and ascertainment bias in single-center reports. ALF occurs in patients of all ages, but the causes and prognosis in adults and in infants and children differ markedly [2], [5]. In addition, for reasons that are
Initial evaluation
The diagnosis of ALF is based on the physical examination (altered mental status) and laboratory findings (INR > 1.5). The initial evaluation should include rapid identification of the underlying cause, with an emphasis on treatable conditions (Table 2). In addition to serologic testing, a urine toxicology screen, and liver imaging, a careful review of all ingested medications is important. ALF occasionally is confused with other clinical entities such as sepsis, systemic disorders with hepatic
Diagnosis of acetaminophen hepatotoxicity
Acetaminophen overdose is the leading cause of ALF in the United States and in other Western countries and recently has been increasing [3], [6]. There are an estimated 60,000 cases of acetaminophen overdose annually, most of which are intentional suicide gestures [11]. Nearly 26,000 patients who have acetaminophen overdose are hospitalized each year; an estimated 1% of these patients develops severe coagulopathy or encephalopathy. The mortality attributed to acetaminophen overdose is 500 per
Management of acetaminophen overdose
Standard medical therapy of known or suspected acetaminophen overdose includes induction of emesis by ipecac syrup, gastric lavage of pill fragments, and administration of activated charcoal to reduce absorption (see Box 1) [24]. In patients who have a single ingestion, the likelihood of subsequent hepatotoxicity is estimated by the Rumack nomogram.
Patients who have known or suspected intentional acetaminophen overdose should be hospitalized to assess their suicidal risk. Patients who have
Unintentional acetaminophen overdose
The ALFSG recently demonstrated that nearly 50% of acetaminophen-related ALF occurs without an overt suicide intent [6]. In most of these patients, the amount of acetaminophen ingested exceeded the maximal daily recommended dose of 4 g/d. Nearly 50% of these patients, however, reported ingesting only 4 to 10 g/d, and 38% of patients ingested a multitude of products. Contrary to earlier reports, these patients were not more likely to be taking antidepressants or to have a history of alcohol
Acute liver failure related to viral hepatitis
Severe acute HAV, HBV, and hepatitis E virus (HEV) infections occasionally produce ALF. The diagnosis of HAV-related ALF depends on the detection of anti-HAV IgM. Young children, persons more than 50 years old, and individuals who have underlying liver disease may be more prone to develop severe acute HAV. The overall incidence of ALF from acute HAV infection is less than 1% [7], [30]. A recent analysis of the United Network for Organ Sharing (UNOS) transplant database and the ALFSG confirmed a
Idiosyncratic drug reactions
Drug-induced liver injury (DILI) is a leading cause for the discontinuation of drugs in development and for regulatory actions on previously approved drugs [45]. DILI is rare (1 in 10,000 to 1 in 1,000,000 patient years) and is thought to be caused by host metabolic idiosyncrasy [46], [47]. Most patients who have severe DILI experience acute hepatocellular injury resulting in jaundice, but some patients develop severe DILI from severe cholestatic hepatic injury [48], [49]. Multiple case series
Metabolic and infiltrative diseases
Wilson's disease is a hereditary disorder of impaired biliary excretion of copper that presents as ALF in up to 25% of adolescent or young-adult patients [74]. Clues to fulminant Wilson's disease include the presence of Kayser-Fleischer rings on slit-lamp examination in up to 50% of cases, low serum alkaline phosphatase levels, hemolytic anemia with hyperbilirubinemia, and low serum ceruloplasmin levels (although these levels are normal in 15% of patients) [75]. Elevated serum and urinary
Indeterminate acute liver failure
No cause is identified in up to 20% of adult patients who have ALF and in 50% of children who have ALF [3], [5], [78]. Prior studies failed to demonstrate occult infection with HBV, HEV, parvovirus B-19, HSV, or SEN virus in US ALFSG adult patients who had indeterminate ALF [33], [43], [79], [80]. Other proposed causes include occult autoimmune hepatitis, undiagnosed acetaminophen hepatotoxicity, or DILI [23]. In the ALFSG, 19% of the patients who had indeterminate ALF had detectable serum
Management of acute liver failure
A key principle in management is the unpredictable and rapid manner in which patients who have ALF can deteriorate. Therefore, patients who have ALF should be monitored in an ICU for frequent neurologic and hemodynamic assessment [2]. If the prognosis is poor, early transfer to a liver transplant center is recommended.
Prognosis in acute liver failure
Before the widespread availability of liver transplantation, the reported survival of patients who had ALF was 3% to 18% [2], [112]. Later studies reported survival of 14% to 25% without liver transplantation and 41% to 49% with liver transplantation [113]. Among transplant recipients, the 1-year patient survival rate now varies between 60% and 80% [114], [115]. The severity of encephalopathy and coagulopathy correlate inversely with survival [116], [117]. Numerous prognostic scales have been
Liver transplantation
Emergency liver transplantation is the only intervention with known survival benefit in patients who have ALF carrying a poor prognosis [114]. Outcome after liver transplantation is linked closely to the severity of the pretransplant illness and the nature of the graft used. Currently, the 1-year survival of patients undergoing transplantation for ALF is lower than that of patients undergoing transplantation for chronic liver failure (70% versus 85%), probably because of the emergent nature of
Artificial and bioartificial liver devices
Artificial and bioartificial liver-support devices are under development for patients who have acute and acute on chronic liver failure. These devices may be ideally suited for patients who have ALF as a bridge to spontaneous recovery during native liver regeneration. The design of a clinical trial design is difficult, however, because of variable spontaneous recovery rates and variable availability of liver transplantation. The ideal liver replacement device should perform normal hepatocyte
Summary
ALF remains a dramatic and highly unpredictable clinical syndrome. Studies of its causes and natural history are hampered by its low incidence, variable terminology, and variable clinical management. In the United States, acetaminophen is the leading cause of ALF, and the incidence of unintentional acetaminophen overdose seems to be increasing. ALF is a clinical syndrome of coagulopathy and encephalopathy ensuing from a multitude of infectious, immunologic, vascular, infiltrative, and metabolic
Acknowledgments
The author would like to acknowledge the contributions and mentorship provided by Dr. William Lee of the University of Texas Southwestern, who is the principal investigator of the Acute Liver Failure Study Group.
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The author was supported in part by NIH grant (UO1 DK058389-07) as a participant in the Acute Liver Failure Study Group.