Hepatic Failure: Complications and Therapy
Acute Liver Failure Including Acetaminophen Overdose

https://doi.org/10.1016/j.mcna.2008.03.005Get rights and content

Acute liver failure (ALF) is a dramatic, highly unpredictable clinical syndrome defined by the sudden onset of coagulopathy and encephalopathy. Acetaminophen overdose, the leading cause of ALF in the United States, has a 66% chance of recovery with early N-acetylcysteine treatment and supportive care. Cerebral edema and infectious complications are difficult to detect and treat in these patients and may cause irreversible brain damage and multiorgan failure. One-year survival after emergency liver transplantation is 70%, but 20% of listed patients die, highlighting the importance of early referral of patients who have ALF with a poor prognosis to a transplant center.

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.

References (136)

  • R.J. Andrade et al.

    Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period

    Gastroenterology

    (2005)
  • G. Danan et al.

    Causality assessment of adverse reactions—a novel method based on conclusions of international consensus meetings: application to drug-induced liver injuries

    J Clin Epidemiol

    (1993)
  • M.I. Lucena et al.

    Comparison of two clinical scales for causality assessment in hepatotoxicity

    Hepatology

    (2001)
  • M.A. Shapiro et al.

    Causality assessment of drug-induced hepatotoxicity: promises and pitfalls

    Clin Liver Dis

    (2007)
  • W.R. Kessler et al.

    Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis

    Clin Gastroenterol Hepatol

    (2004)
  • L. Weinstein

    Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy

    Am J Obstet Gynecol

    (1982)
  • S.P. Pereira et al.

    Maternal and perinatal outcome in severe pregnancy-related liver disease

    Hepatology

    (1997)
  • P. Fickert et al.

    Acute Budd-Chiari syndrome with fulminant hepatic failure in a pregnant woman with factor V Leiden mutation

    Gastroenterology

    (1996)
  • C.N. Broussard et al.

    Mushroom poisoning—from diarrhea to liver transplantation

    Am J Gastroenterol

    (2001)
  • A.S. Klein et al.

    Amanita poisoning: treatment and the role of liver transplantation

    Am J Med

    (1989)
  • E.A. Roberts et al.

    American Association for the Study of Liver Disease practice guidelines: a practice guideline on Wilson disease

    Hepatology

    (2003)
  • E.F.M. Wijdicks et al.

    Clinical and radiologic features of cerebral edema in fulminant hepatic failure

    Mayo Clin Proc

    (1995)
  • R. Jalan

    Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure

    Neurochem Int

    (2005)
  • F.S. Larsen et al.

    Functional loss of cerebral blood flow autoregulation in patients with fulminant hepatic failure

    J Hepatol

    (1995)
  • G. Strauss et al.

    Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure

    J Hepatol

    (1998)
  • R. Jalan et al.

    Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia

    Hepatology

    (2001)
  • C. Trey et al.

    The management of fulminant hepatic failure

  • J.P. Polson et al.

    American Association for the Study of Liver Disease position paper: the management of acute liver failure

    Hepatology

    (2005)
  • G.A. Ostapowicz et al.

    Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

    Ann Intern Med

    (2002)
  • J.H. Hoofnagle et al.

    Fulminant hepatic failure: summary of a workshop

    Hepatology

    (1995)
  • R.H. Squires et al.

    Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group

    J Pediatr

    (2006)
  • A.M. Larson et al.

    Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study

    Hepatology

    (2005)
  • R.M. Taylor et al.

    Fulminant hepatitis A virus in the United States: incidence, prognosis, and outcomes

    Hepatology

    (2006)
  • H. Ring-Larsen et al.

    Renal failure in fulminant hepatic failure and terminal cirrhosis: a comparison between incidence, types, and prognosis

    Gut

    (1981)
  • P. Nourjah et al.

    Estimates of acetaminophen (Paracetamol)-associated overdoses in the United States

    Pharmacoepidemiol Drug Saf

    (2006)
  • R.J. Fontana et al.

    “Unintentional” acetaminophen overdose on the rise: who is responsible?

    Can J Gastroenterol

    (2006)
  • M.J. Smilkstein et al.

    Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976–1985)

    N Engl J Med

    (1988)
  • E.K. Kuffner et al.

    Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial

    Arch Intern Med

    (2001)
  • D.C. Whitcomb et al.

    Association of acetaminophen hepatotoxicity with fasting and alcohol use

    JAMA

    (1994)
  • P.B. Watkins et al.

    Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily

    JAMA

    (2006)
  • F.V. Schiodt et al.

    Acetaminophen toxicity in an urban county hospital

    N Engl J Med

    (1997)
  • B.H. Rumack

    Acetaminophen hepatotoxicity: the first 35 years

    J Toxicol Clin Toxicol

    (2002)
  • J. Polson et al.

    Elevated bilirubin may cause false positive acetaminophen levels in hepatitis patients

    Hepatology

    (2004)
  • L.P. James et al.

    Acetaminophen-induced hepatotoxicity

    Drug Metab Dispos

    (2003)
  • N. Kaplowitz

    Acetaminophen hepatotoxicity: what do we know, what we don't know, and what do we do next?

    Hepatology

    (2004)
  • K. Hawton et al.

    Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study

    BMJ

    (2001)
  • K. Hawton et al.

    UK legislation in analgesic packs: before and after study of long term effect on poisonings

    BMJ

    (2004)
  • Food and Drug Administration, 21 CRF Parts 201 and 343

    Internal analgesic, antipyretic, and antirheumatic drug products for over the counter human use: proposed amendment of the tentative final monograph, required warnings and other labeling

    Federal Register

    (2006)
  • Recommended adult immunization schedule—United States October 2006–September 2007

    MMWR

    (2006)
  • C.T. Wai et al.

    Clinical outcome and virological characteristics of hepatitis B related acute liver failure in the United States

    J Viral Hepat

    (2005)
  • Cited by (192)

    • Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver Failure

      2024, Cellular and Molecular Gastroenterology and Hepatology
    • Drug-Induced Liver Injury

      2022, Comprehensive Pharmacology
    • Traditional herbal medicine, pharmacognosy, and pharmacopoeial standards: A discussion at the crossroads in the age of COVID

      2022, Evidence-Based Validation of Herbal Medicine: Translational Research on Botanicals
    View all citing articles on Scopus

    The author was supported in part by NIH grant (UO1 DK058389-07) as a participant in the Acute Liver Failure Study Group.

    View full text