Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overre-presentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. Conclusion DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival.

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.

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 g/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio > 2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. In conclusion, conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.

A method has been developed for routine high yield separation of canalicular (cLPM) from basolateral (bILPM) liver plasma membrane vesicles of rat liver. Using a combination of rate zonal floatation (TZ-28 zonal rotor, Sorvall) and high speed centrifugation through discontinuous sucrose gradients, 9-16 mg of cLPM and 15-28 mg of bILPM protein can be isolated in 1 d. cLPM are free of the basolateral markers Na+/K+-ATPase and glucagonstimulatable adenylate cyclase activities, but are highly enriched with respect to homogenate in the "canalicular marker" enzyme activities leucylnaphthylamidase (48-fold), -y-glutamyltranspeptidase (60-fold), 5'-nucleotidase (64-fold), alkaline phosphatase (71-fold), Mg*+-ATPase (83-fold), and alkaline phosphodiesterase I (116-fold) . In contrast, bILPM are 34-fold enriched in Na+/K+-ATPase activity, exhibit considerable glucagon-stimulatable adenylate cyclase activity, and demonstrate a 4-to 15-fold increase over homogenate in the various "canalicular markers ." cLPM have a twofold higher content of sialic acids, cholesterol, and sphingomyelin compared with bILPM . At least three canalicular-(130,000, 100,000, and 58,000 mol wt) and several basolateral-specific protein bands have been detected after SDS PAGE of the two LPM subtractions . Specifically, the immunoglobin A-binding secretory component is restricted to bILPM as demonstrated by immunochemical techniques. These data indicate virtually complete separation of basolateral from canalicular LPM and demonstrate multiple functional and compositional polarity between the two surface domains of hepatocytes .Hepatocytes like other secretory cells represent highly polarized units containing three morphologically and functionally distinct surface domains (1, 2). The sinusoidal front, characterized by numerous microvilli extending into the space of Disse, provides for efficient exchange of various ions, organic solutes, and proteins with the blood (3, 4). The lateral surface, in contact with neighboring hepatocytes, is specialized for cell adhesion and intracellular communications and is characterized by tight junctions, desmosomes, and gap junctions (5). Since both the sinusoidal front and the lateral surface (i.e., the "basolateral" pole of hepatocytes) are in physical continuity and directly exposed to sinusoidal blood plasma, these two plasma membrane domains are thought to be functionally equivalent (1_6). In contrast, the bile canalicular or apical pole of the cell, which accounts for only 13% of the plasma membrane surface area, is separated from the plasma space by tight junctional complexes . These tight junctions encircle THE JOURNAL OF CELL BIOLOGY " VOLUME 98 MARCH 1984991-1000 0 The Rockefeller University Press -0021-9525/84/03/0991/10 $1 .00 the hepatocyte like a belt or girdle (2) . They exhibit only limited permeability to small plasma solutes and effectively prevent the regurgitation of bile components into blood. Within the minute channels ofbile canaliculi, the canalicular membranes are folded into microvill...

The prevalence of EV in cirrhosis increases with the severity of liver disease, as expected. Thrombocytopenia and splenomegaly are independent predictors of large EV in cirrhosis. Further prospective studies might result in a discriminating algorithm to predict which patients with cirrhosis would benefit from early or regular endoscopy to detect clinically significant varices.