Acetaminophen, the most widely used analgesic in the United States, causes severe hepatic necrosis leading to acute liver failure (ALF) after suicidal overdoses.1–3 Unintentional liver injury from self-medication for pain or fever that leads to daily doses exceeding the 4 g/day package recommendations is also well-recognized.4–7 Fasting and alcohol use may enhance toxicity, but this remains controversial.6, 8N-acetylcysteine (NAC) can prevent hepatic injury if given within 12 hours of a single ingestion. However, unintentional overdosing is usually only recognized after symptoms have developed. Extended acetaminophen dosing, delay in seeking medical attention, and/or failure to institute NAC therapy are associated with greater morbidity and mortality.9, 10 In retrospective studies, poorer outcomes also have been reported for subjects with unintentional acetaminophen overdose, but these data are incomplete.4–7

Before the 1980s, acetaminophen was not mentioned as a cause in case series of ALF.11, 12 A U.S. retrospective study from 1994 to 1996 found a 20% incidence of acetaminophen toxicity leading to ALF.13 In January 1998, we began to examine prospectively the epidemiology and outcomes of all forms of ALF in the United States at the centers participating in the Acute Liver Failure Study Group (ALFSG). In the current study, we investigated the incidence, risk factors, and outcomes of a cohort of 275 consecutive U.S. patients with acetaminophen-related ALF enrolled in the ALFSG registry over 6 calendar years from start of study through December 31, 2003. Based on earlier observations, we hypothesized that patients with unintentional acetaminophen overdose would present with more severe disease [higher international normalized ratio (INR), APACHE score, stage 3 or 4 encephalopathy], more frequently suffer from alcohol abuse, and have a poorer rate of spontaneous transplant-free survival compared with intentional overdose patients.14

Patients and Methods

Between January 1, 1998, and December 31, 2003, demographic, clinical, laboratory, and outcome information were prospectively recorded on all subjects meeting entry criteria for ALF at the 22 academic centers participating in the ALFSG. By definition, eligible patients had an INR ≥1.5, evidence of hepatic encephalopathy,15 and presented within 26 weeks of illness onset without apparent chronic liver disease.13 Because subjects were encephalopathic (per definition), written informed consent was obtained from their legal next of kin. Data were collected on an admission case report form and subsequently on a separate study outcome form, with outcome defined as liver transplantation, discharge, or 3 weeks after admission.16 All centers were in compliance with their local institutional review board requirements. A Certificate of Confidentiality was obtained from the National Institutes for Mental Health for the entire study.

A careful history of acetaminophen ingestion was elicited where possible for each patient, including total dose, type of acetaminophen product taken, and duration of use. Criteria for assigning acetaminophen as the cause of ALF were: (1) a history of potentially toxic acetaminophen ingestion (i.e., >4 g/day, the maximum dose recommended on the package) within 7 days of presentation; (2) detection of any level of acetaminophen in the serum; or (3) a serum alanine aminotransferase (ALT) >1,000 IU/L with a history of acetaminophen ingestion, irrespective of the acetaminophen level. Exclusion of competing causes of ALF was also required, including acute hepatitis A and B, hepatic ischemia, autoimmune hepatitis, and Wilson disease, among other etiologies.16 Criteria for listing and proceeding with liver transplantation were those used at each clinical center. Case report forms were reviewed by investigators at the central site (UTSW) to confirm the diagnosis, and annual on-site audits were conducted by the central site as well.

Results

Overall Study Population

Of the 662 ALF subjects enrolled during the 6-year study period, 302 (46%) were reported to have acetaminophen-related hepatotoxicity. Twenty-seven were excluded after further review: in 10, the most likely cause was acetaminophen but data were insufficient and no other cause was evident. In 17 patients, competing causes such as viral hepatitis, concomitant polydrug use, or shock were identified. The remaining 275 subjects (42%) constituted the final study group. Over the study period, the percentage of ALF cases attributed to acetaminophen increased from 28% in 1998 to 51% in 2003 (Fig. 1). The number and percentage of ALF cases attributed to acetaminophen for the 6-year period far exceeded any other category, with 12% of cases attributed to idiosyncratic drug-induced hepatotoxicity (prescription drugs, herbs) and 19% considered indeterminate with no discernible cause after complete evaluation.

Discussion

Acetaminophen poisoning has become the most common cause of ALF in both the United States and the United Kingdom.13, 20–22 Underreporting may have occurred in the past when transplant databases were used.13, 22 Nevertheless, current data suggest a dramatic increase in acetaminophen toxicity recently; the percentage of all ALF cases in our registry that were due to acetaminophen has nearly doubled in 6 years. Although they are less frequent in terms of overall acetaminophen-related hospitalizations, unintentional overdoses constitute at least half of all those that develop encephalopathy.7 Intentional and unintentional cases have similar clinical pictures and outcomes once the threshold of ALF has been reached. In many subjects, multiple factors appear to be at play, including repeated dosing in excess of package labeling, use of multiple acetaminophen-containing products, simultaneous use/abuse of alcohol and narcotics, and depression. Patients with chronic pain appear to be particularly susceptible to this problem.

Although our study included consecutive subjects studied prospectively, it has several limitations. First, we portray here only the most severely ill subjects who meet criteria for ALF.7 In addition, our group may not represent the true incidence of ALF in the population at large, because many patients are not referred to transplant centers because of failure to diagnose ALF, presumption of mild disease, suicide or substance abuse histories, poor prognosis (cancer patients, the elderly), or unsuitability for liver transplantation.14 Our patients were evaluated by experienced hepatologists, and the history of all drug and alcohol ingestion was determined carefully. Nevertheless, patients by definition have altered mentation, making accurate history-taking difficult or impossible. For example, obtaining a recent food or alcohol intake history immediately before hospitalization was not feasible. More than 80% of patients were transferred from other institutions, often after significant encephalopathy had set in, compromising history (i.e., time of last dose, total dose ingested, etc.).

Our study sites, representing approximately 30% of U.S. transplant capability (United Network for Organ Sharing data), recorded an average of 49 acetaminophen-related liver failure cases/year over the 6-year period. Based on data from site enrollment logs, an additional 40% of cases were not enrolled because of lack of informed consent or inadequate information to ensure the diagnosis (data not shown). Thus, we estimate that at least 250 cases of acetaminophen-related ALF are seen annually at U.S. transplant centers, resulting in approximately 73 deaths. This is considerably less than the estimated 458 deaths per year attributable to acetaminophen poisoning predicted by the FDA, possibly reflecting lack of referral for transplant of suicidal or substance-abuse patients. Nevertheless, a high proportion of our patients who were referred to a transplant center demonstrated substance abuse or major psychiatric problems. Of interest, data from a large national survey suggest that 36% of Americans ingest an acetaminophen-containing compound at least once a month; this figure underscores the low incidence of ALF due to acetaminophen overdose compared with the millions of tablets consumed on a daily basis.23

One of the most alarming findings in our study was that unintentional acetaminophen overdose accounted for 50% of our cases. The rate of unintentional overdose was estimated to be 31% in Australia, and nonsuicidal overdoses are only rarely reported in the United Kingdom and Europe.24–26 Single timepoint ingestions with suicidal intent constituted 70% of all hospitalized subjects in one U.S. series, but these subjects frequently presented early after ingestion when use of NAC would be effective, so that few developed encephalopathy and only 2% died.7 In the current series, in which cases were limited to those subjects reaching the threshold of encephalopathy, the mortality rate was higher (approximately 29%) and similar for the intentional and unintentional groups. Whereas unintentional cases uniformly present after symptoms have developed, those with suicidal intent who develop encephalopathy typically have other cofactors such as use of alcohol, narcotics, or sedatives that may delay presentation or enhance toxicity.

We have been careful to describe the features of the unintentional group because their incidence differs markedly from the experience in other countries. Amongst unintentional overdose patients, most (79%) reported that they were taking the medication(s) specifically for pain or constitutional symptoms (8%). Many claimed to have ingested modest amounts of acetaminophen over weeks or months, with 63% reporting use of narcotic combinations.4, 6, 27–29 Why, then, the sudden onset of severe liver injury? Our data suggest that there is a narrow therapeutic margin and that consistent use of as little as 7.5 g/day may be hazardous. However, precise information on dosing is often difficult to acquire in some of these patients. We are planning to look at this issue in more detail in a future study. Late presentation is undoubtedly a factor in the unintentional cases as described in this study and previously,7 but the acuity of the unintentional cases (height of ALT levels, severity ofillness) was similar to single timepoint ingestions. The development of tolerance to gradually increasing doses of acetaminophen has been reported previously in association with narcotic abuse.27 Worsening pain may occasion the supra-normal dosing in the days before admission. Alternatively, loss of tolerance may result from alcohol use, starvation, or inter-current illness leading to glutathione depletion.6 In spite of long-term ingestion histories, the cases that reported >7 days' ingestion still had an acute injury, in terms of their biochemical values, that was indistinguishable from suicidal ingestions, suggesting that there is no chronic form of injury, but rather a threshold of safety that may be breached with devastating results. Toxicological testing, while performed in a limited number of patients, strongly suggested use of illicit drugs, although the information available included illegal as well as legal narcotic use. There was no impact observed for lower socioeconomic groups in the acetaminophen group because no difference in level of education was evident between the acetaminophen groups and other forms of ALF. Some may have had genetic polymorphisms making them more susceptible to acetaminophen poisoning at lower doses, but most had ingested doses that would be expected to cause severe liver injury.30, 31

A second potential reason for toxicity is the simultaneous use of 2 preparations, recorded in 22% overall, and 38% of the unintentional group. Information was not available regarding the reason for the use of 2 preparations, but frustration, impulsivity, or simply lack of recognition of the presence of acetaminophen in both preparations have all been recognized.32 Of interest, a third of narcotic users were simultaneously ingesting an over-the-counter acetaminophen product (data not shown). This suggests patients' lack of awareness of the hazards of over-the-counter acetaminophen use in combination with prescribed agents.32 An independent interview evaluation after patients have recovered might help in establishing exact dosages, reasons for excess ingestion, and patient understanding of the implications of overdosing on this ubiquitous but hazardous medication.33

A full third of our subjects met standard criteria for alcohol abuse (i.e., >40 g/day in men and >20 g/day in women). These subjects less often used acetaminophen/narcotic compounds or antidepressants, suggesting that they may have been self-medicating with alcohol. Their acetaminophen levels were lower, despite reporting intake of similar amounts of acetaminophen. Because the subjects with ALF reporting use of ≤4 g acetaminophen per day were often alcohol abusers (65%) and the amount of daily alcohol consumed was greater than that reported by patients who admitted to taking >4 g acetaminophen per day (data not shown), ethanol may still serve as an important co-factor in these lower-dose subjects.4, 6, 13, 24, 34–36

The overall transplant-free survival rate of 65% in acetaminophen subjects is comparable to that of prior studies and continues to be more favorable than that observed for most other ALF causes.13, 37, 38, 39 The use of the King's criteria at admission to predict outcome was inaccurate, and use of the APACHE II provided a more accurate of assessment outcome. Clearly, improved prognostic criteria are needed.22, 39, 40

In conclusion, acetaminophen poisoning now accounts for at least 42% of U.S. acute liver failure cases seen at tertiary-care centers and one third of the deaths. Unintentional overdose is the leading form of acetaminophen hepatotoxicity in U.S. ALF subjects, but suicidal ingestions remain important as well. Susceptible patients include those with chronic pain, depression, and substance abuse, including alcohol. Legislative changes in the United Kingdom leading to restrictions in the sales of acetaminophen have reduced the number of patients dying from or needing transplantation because of acetaminophen hepatotoxicity.33, 41–46 Because most cases in the United Kingdom are considered to be suicidal, they differ in that sense from unintentional cases. Nevertheless, efforts to limit OTC package size and to restrict the prescription of narcotic–acetaminophen combinations (or to separate the narcotic from the acetaminophen) may be necessary to reduce the incidence of this increasingly recognized but preventable cause of ALF in the United States. Educational programs for practicing physicians, pharmacists, and consumers, involving a full discussion of the hazards of this ubiquitous pain reliever and the identification of susceptible groups, seems warranted.

Acknowledgements

The authors thank all the nurses, investigators, and house staff who tirelessly work to make this study possible.

Appendix