Background Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction without prior advanced liver disease that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. Objective To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. Design Prospective observational cohort study. (ClinicalTrials.gov: NCT00518440) Setting 31 liver disease and transplant centers in the United States. Patients Consecutively enrolled patients–without prior advanced liver disease–with ALF (n = 2070). Measurements Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). Results Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. Limitations The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. Conclusion Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. Primary Funding Source National Institutes of Health.

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OBJECTIVES Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10× elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10× elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

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