News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD, FAAFP
Authors and Disclosures
Released: 07/15/2009; Valid for credit through 07/15/2010
July 15, 2009 — Although drug-induced acute liver failure (DIALF) is very rare, it can be fatal, according to the results of a retrospective cohort study reported in the July issue of Liver Transplantation.
"Acute liver failure (ALF) is an uncommon but potentially lethal drug-related adverse effect that often leads to liver transplantation (LT) or death," write Ayse L. Mindikoglu, from the University of Maryland School of Medicine in Baltimore, and colleagues. "It is also the leading cause of regulatory action, including withdrawal of drugs from the market, restrictions in indications, and warnings to healthcare providers and patients, in the United States over the past 5 decades."
Using the United Network for Organ Sharing Standard Transplant Analysis and Research files, the investigators identified and analyzed data from 661 patients (567 adults and 94 children < age 18 years) who underwent liver transplantation for DIALF from October 1, 1987, through December 31, 2006. Data were analyzed for 20 recipient and 6 donor demographic and clinical variables.
The 4 drug groups most often responsible for DIALF were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). Estimated 1-year survival rates were 76% for acetaminophen, 82% for antituberculosis drugs, 52% for antiepileptics, 82% for antibiotics, and 79% for DIALF caused by other drugs.
For antiepileptic-induced ALF, the lower survival rate was attributed mostly to deaths in children, with a mortality rate of 73% within the first year among the 22 patients younger than 18 years who had ALF caused by antiepileptics, These patients were also least likely to be listed as status 1, spent the most time waiting on the transplant list, and had the longest warm and cold ischemia times. However, controlling for these variables in multivariate analysis did not change the relatively low survival probability in this patient subgroup.
Although overall survival rate was statistically similar for acetaminophen-related and non–acetaminophen-related ALF, the former group required dialysis before liver transplantation at a significantly higher rate than all other drug groups (27% vs 3% - 10%; P < .0001).
The need for life support, DIALF caused by antiepileptic drugs at age younger than 18 years, and elevated serum creatinine levels were independent pretransplant predictors of death after liver transplantation, based on Cox proportional hazards regression analysis. The investigators derived a mathematical prognostic model that showed strong predictive ability in the entire study population.
"The leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics," the study authors write. "Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen-related ALF required dialysis at a significantly higher rate."
Limitations of this study include inability to determine causality and small pediatric sample.
In an accompanying editorial, Paul H. Hayashi, from the University of North Carolina at Chapel Hill, and Paul B. Watkins, from the Institute for Drug Safety at the Hamner Institutes of Health Sciences, Research Triangle Park, North Carolina, recommend more focused research on drug-induced liver injury in pediatric populations. They also note that the clinical usefulness of the predictive model, if validated, may be limited.
"Large registries such as the UNOS [United Network for Organ Sharing] database provide valuable population-based data to form hypotheses, but they lack all desired phenotypic information about the patients," the editorialists conclude. "Multicenter studies such as the Acute Liver Failure Study Group and Drug Induced Liver Injury Network can provide detailed individual patient data, sera, and genomic DNA, which can be used to investigate these new hypotheses. The combined efforts will hopefully shed better light on preventive factors, including genetic predisposition, and move us beyond simply reporting cases and case series."
The Health Resources and Services Administration supported this study. The content does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. One of the study authors is employed by Eli Lilly.
Liver Transpl. 2009;15:675-676, 719-729.
Multiple medications can negatively affect liver function, and drug toxicity is the most common reason for ALF in the United States among both adults and children between the ages of 3 and 18 years. Acetaminophen is the most commonly implicated drug to promote DIALF, and previous research suggests that patients with DIALF secondary to acetaminophen are less likely to receive a liver transplantation vs DIALF related to other drugs. However, 1-year survival rates after liver transplantation are good for both groups of patients.
The current study uses a large patient database to further analyze the etiology and prognosis of DIALF requiring liver transplantation.
• The study used a national database of liver transplantation patients in the United States. The current analysis focused on patients receiving a transplant for DIALF between 1987 and 2006.
• Researchers examined 20 pretransplantation variables related to the liver recipient, along with 6 donor variables.
• The main outcomes of the study were the reason for DIALF, survival rates at 1 year after liver transplantation, and variables associated with a worse prognosis after liver transplantation. A multivariate analysis was performed to adjust for covariates that affected this outcome.
• Of 73,977 patients who underwent liver transplantation, 661 had a diagnosis of DIALF. DIALF was the diagnosis in 12% of patients who underwent liver transplantation for ALF.
• 567 of the 661 patients analyzed were adults. The mean age of the entire cohort was 36 years, and there were more women than men in the cohort.
• The 4 leading drugs implicated in DIALF were acetaminophen (40% of all patients), antituberculosis medications (8%), antiepileptics (7%), and antibiotics (6%).
• The mean serum creatinine level was higher among patients with DIALF secondary to acetaminophen, and these patients were also more likely to require dialysis and life support.
• The mean serum total bilirubin level was highest among patients with DIALF related to the use of antibiotics.
• The median survival time for the entire cohort was 14.4 years.
• 1-year estimated survival probabilities among subjects with DIALF because of acetaminophen, antituberculosis medications, antiepileptics, antibiotics, and other drugs were 76%, 82%, 52%, 82%, and 79%, respectively.
• Children and adolescents younger than 18 years experienced particularly low 1-year survival duration after DIALF secondary to antiepileptic drugs (27%).
• Patients with DIALF secondary to antiepileptic drugs were also more likely to require a subsequent liver transplant.
• After regression analysis, independent pretransplant variables associated with a higher risk for mortality after liver transplantation were life support treatment, DIALF because of antiepileptic drugs before age 18 years, and elevated serum creatinine levels.
• Drug toxicity is the most common reason for ALF in the United States among both adults and children between the ages of 3 and 18 years. Acetaminophen is the most commonly implicated drug to promote DIALF, and previous research suggests that 1-year survival rates after liver transplantation for DIALF exceed 75%.
• In the current study, factors associated with a higher rate of mortality after liver transplantation for DIALF included life support treatment, DIALF because of antiepileptic drugs before age 18 years, and elevated serum creatinine levels.
Which of the following statements regarding the epidemiology and prognosis of DIALF is most accurate?
□Drug toxicity is the most common cause of ALF among adults in the United States
□Drug-induced liver injury is not a significant problem among children
□Antiepileptic medications are the most common cause of DIALF
□One-year survival rates after liver transplantation for DIALF are less than 20%
In the current study by Mindikoglu and colleagues, all of the following variables were associated with a higher risk for mortality after liver transplantation for DIALF except:
□Elevated serum creatinine levels
□Elevated serum bilirubin levels
□Life support treatment
□DIALF secondary to antiepileptic drugs among children and adolescents
1.Which of the following statements regarding the epidemiology and prognosis of DIALF is most accurate?
Answer: Drug toxicity is the most common cause of ALF among adults in the United States
Drug toxicity is the most common reason for ALF in the United States among both adults and children between the ages of 3 and 18 years. Acetaminophen is the most commonly implicated drug to promote DIALF, and previous research suggests that 1-year survival rates after liver transplantation for DIALF exceed 75%.
2.In the current study by Mindikoglu and colleagues, all of the following variables were associated with a higher risk for mortality after liver transplantation for DIALF except:
Answer: Elevated serum bilirubin levels
In the current study, factors associated with a higher rate of mortality after liver transplantation for DIALF included life support treatment, DIALF because of antiepileptic drugs before age 18 years, and elevated serum creatinine levels.