“Unintentional” Acetaminophen Overdose on the Rise: Who is Responsible?

Dr Fontana has been a leading investigator in the US Acute Liver Failure Study Group (ALFSG) for the past eight years.He is currently the Chair of the Ancillary Studies Committee and principal investigator of the long-term outcomes study of ALFSG patients.Dr Fontana is also a site investigator at the National Institutes of Health Drug Induced Liver Injury Network, which is prospectively enrolling patients with idiosyncratic drug hepatotoxicity due to prescription or complementary and alternative medicines (see http://dilin.dcri.duke.edu/for further information).PA: Tell us about the US ALFSG.RJF: The US ALFSG is a network of 23 clinical sites and investigators interested in improving our understanding of the causes and outcomes of acute liver failure (ALF).Because ALF is an uncommon illness in western countries, with an estimated annual incidence of only one per 100,000 (ie, 2500 cases per year in the US), a multicentre network of referral centres provides a practical means to study this rare but potentially devastating illness.The University of Texas Southwestern Medical Center at Dallas (US), under the leadership of William Lee, MD serves as the lead site and datacoordinating centre.We currently have an ongoing therapeutic trial of intravenous N-acetylcysteine versus placebo for non-acetaminophen (ACM)-induced ALF, and there are tentative plans to conduct a future study of moderate hypothermia in ALF patients with advanced encephalopathy.Recently, the adult ALFSG was renewed as a National Institutes of Health cooperative agreement through 2010, and Canada is now represented through the University of Toronto (Toronto, Ontario) with Les Lilly, MD as the site investigator.Consecutive patients with ALF (ie, international normalized ratio greater than 1.5 and encephalopathy onset within 26 weeks of presentation) are enrolled in the prospective observational study and followed for three weeks until recovery, transplantation or death.Detailed clinical data at presentation, serum, urine and liver tissue samples, and DNA for genetic testing have been collected in over 1000 adults since the study was initiated in 1998.Analysis of the first 308 patients enrolled demonstrated that ACM was the most common cause of ALF, accounting for 39% of cases, followed by a potpourri of idiosyncratic drug reactions in 13% (1).Interestingly, severe acute hepatitis A virus (HAV) and hepatitis B virus (HBV) infection accounted for only 4% and 7% of ALF, respectively, while 17% of cases were of indeterminate etiology.Overall, patient survival was 67% at three weeks, and 29% required emergency liver transplantation.The high proportion of ACM-induced ALF is in marked distinction to studies from the 1970s and 1980s, in which HAV and HBV were the most common etiologies of ALF, and ACM was not even mentioned (2,3).The shift in etiologies may be due to differing study methods, a reduced incidence of HAV/HBV due to vaccination, and increasing use of ACMcontaining products versus acetylsalicylic acid for acute febrile illnesses in both children and adults to minimize the risk of Reye's syndrome.The extensive clinical and laboratory data, as well as the bank of serum and DNA samples, have provided a unique opportunity to conduct many important ancillary studies.Currently, there are over 40 active ancillary studies investigating topics ranging from laboratory and clinical predictors of susceptibility and liver regeneration to natural history and longterm neurological outcomes.We recently demonstrated that occult HBV, hepatitis E virus, SEN-V and parvovirus B19 infection do not account for the large proportion of indeterminate ALF cases (4-6).In addition, we learned that ALF patients with intracranial pressure monitors receive more interventions and undergo liver transplantation more frequently than nonmonitored patients, but they did not experience improved survival (7).I am hopeful that the ALFSG will continue to make important scientific contributions to our understanding of the etiopathogenesis and outcomes of this challenging disease.PA: A recent study from the US ALFSG suggested that 48% of patients with ACM-induced ALF were taking medicinal or therapeutic doses rather than suicidal doses.Can you elaborate on these intriguing findings?RJF: We recently published the outcomes of 275 consecutive patients with ACM-related ALF (8).First, we noted an "Unintentional" acetaminophen overdose on the rise:Who is responsible?

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