US Acute Liver Failure Study Research Articles

A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure

Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC= 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC= 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

Role of Hepatitis E Virus Infection in North American Patients With Severe Acute Liver Injury.

INTRODUCTION:The aim of this study was to determine the role of hepatitis E virus (HEV) infection in a large cohort of prospectively enrolled patients with severe acute liver injury (ALI).METHODS:Serum samples from 594 consecutive adults enrolled between 2008 and 2018 in the US Acute Liver Failure Study Group ALI registry were tested for anti-HEV IgM and anti-HEV IgG levels. Those with detectable anti-HEV IgM underwent further testing for HEV RNA using real-time polymerase chain reaction.RESULTS:The median age of patients was 38 years; 41% were men and 72% Caucasian. Etiologies of ALI included acetaminophen hepatotoxicity (50%), autoimmune hepatitis (8.9%), hepatitis B virus (8.9%), and idiosyncratic drug-induced liver injury (7.9%). Overall, 62 patients (10.4%) were negative for anti-HEV IgM but positive for IgG, whereas only 3 men (0.5%) were positive for both anti-HEV IgM and IgG. These 3 cases were initially diagnosed as having indeterminate, HEV, and hepatitis B virus-related ALI. One of these patients had detectable HEV RNA genotype 3, and another anti-HEV IgM+ patient had detectable HEV antigens by immunohistochemistry on liver biopsy. On multivariate modeling, older (odds ratio: 1.99) and non-Caucasian subjects (odds ratio: 2.92) were significantly more likely to have detectable anti-HEV IgG (P < 0.0001).DISCUSSION:Acute HEV infection is an infrequent cause of ALI in hospitalized North American adults. The anti-HEV IgG+ patients were significantly older and more likely to be non-Caucasian. These data are consistent with other population-based studies that indicate exposure to HEV in the general US population is declining over time and might reflect a cohort effect.

The macrophage activation marker soluble CD163 is elevated and associated with liver disease phenotype in patients with Wilson\u2019s disease

BackgroundMacrophages play a significant role in liver disease development and progression. The macrophage activation marker soluble (s)CD163 is associated with severity and prognosis in a number of different acute and chronic liver diseases but has been only sparsely examined in Wilson’s disease (WD). We investigated sCD163 levels in patients with acute and chronic WD and hypothesized associations with liver disease phenotype and biochemical markers of liver injury.MethodsWe investigated sCD163 in two independent cohorts of WD patients: 28 patients with fulminant WD from the US Acute Liver Failure (ALF) Study Group registry and 147 patients with chronic disease from a German WD registry. We included a control group of 19 healthy individuals. Serum sCD163 levels were measured by ELISA. Liver CD163 expression was determined by immunohistochemistry.ResultsIn the ALF cohort, median sCD163 was 10-fold higher than in healthy controls (14.6(2.5–30.9) vs. 1.5(1.0–2.7) mg/L, p < 0.001). In the chronic cohort, median sCD163 was 2.6(0.9–24.9) mg/L. There was no difference in sCD163 according to subgroups based on initial clinical presentation, i.e. asymptomatic, neurologic, hepatic, or mixed. Patients with cirrhosis at the time of diagnosis had higher sCD163 compared with those without cirrhosis (3.0(1.2–24.9) vs. 2.3(0.9–8.0) mg/L, p < 0.001); and both cohorts significantly lower than the ALF patients. Further, sCD163 correlated positively with ALT, AST, GGT and INR (rho = 0.27–0.53); and negatively with albumin (rho = − 0.37), (p ≤ 0.001, all). We observed immunohistochemical CD163 expression in liver tissue from ALF patients.ConclusionsAlthough sCD163 is not specific for WD, it was elevated in WD patients, especially in those with ALF. Further, sCD163 was higher in patients with cirrhosis compared to patients without cirrhosis and associated with biochemical markers of liver injury and hepatocellular function. Thus, macrophage activation is evident in WD and associates with liver disease phenotype and biochemical parameters of liver disease. Our findings suggest that sCD163 may be used as a marker of liver disease severity in WD patients.

Outcomes of Acute Liver Injury in Adults Due to Wilson's Disease: Is Survival Without Transplant Possible?

Wilson's disease (WD) is a rare cause of acute liver failure (ALF) that is thought to have a uniformly fatal outcome without liver transplantation (LT). Previous studies proposed diagnostic and prognostic criteria for WD-ALF. It is not known whether these apply to WD patients presenting as severe acute liver injury (ALI) without encephalopathy. From 2008 to 2018, 822 patients with ALI in the US Acute Liver Failure Study Group (ALFSG) registry were enrolled and prospectively followed. The diagnosis of WD-ALI was confirmed in 8 patients. Serum biochemical diagnostic ratios predicting WD-ALF (alkaline phosphatase [ALP]:total bilirubin(TB) and aspartate aminotransferase [AST]:alanine aminotransferase [ALT]) were determined in these patients, and predictors of prognosis for WD-ALI were evaluated. Of these 8 ALI-WD patients, 5 received an LT. Ratios of both ALP:TB of <4 and AST:ALT of >2.2 on study admission were met in 4 LT patients. All LT patients were female. The Model for End-Stage Liver Disease scores on admission were generally higher in LT patients. All transplanted patients had an initial revised WD score of >11 (>10 predicting poor outcome without LT in WD-ALF), whereas in non-LT patients, 2 had scores of 9, and 1 a score of 13. Also, 3 LT patients were started on chelation therapy, 2 were started on plasmapheresis, and 1 was started on Molecular Adsorbent Recirculating System therapy. All non-LT patients were treated with chelation. At 21days, all patients were alive and discharged from the hospital. In conclusion, some patients with ALI due to WD may survive without LT. Revised Wilson index scores >10 predict poor outcome in most patients with WD-ALI, as they do for WD-ALF, and they correlate positively with the ALI model in this cohort. Biochemical ratios for WD diagnosis appear more applicable to ALF compared with WD-ALI.

Significant lung injury and its prognostic significance in acute liver failure: A cohort analysis.

Respiratory failure complicating acute liver failure (ALF) may preclude liver transplantation (LT). We evaluated the association between significant lung injury (SLI) and important clinical outcomes. Retrospective cohort study of 947 ALF patients with chest radiograph (CXR) and arterial blood gas (ABG) data enrolled in the US Acute Liver Failure Study Group (US-ALFSG) from January 1998 to December 2016. SLI was defined by moderate hypoxaemia (Berlin classification; PaO2 /FiO2 <200mmHg) and abnormalities on CXR. Primary outcomes were 21-day transplant-free survival (TFS) and overall survival. Of 947 ALF patients, 370 (39%) had evidence of SLI. ALF patients with SLI (ALF-SLI) had significantly worse oxygenation than controls on admission (median PF ratio 120 vs 300mmHg, P<.0001) and higher lactate (6.1 vs 4.6mmol/l, P=.0008). ALF-SLI patients had higher rates of tracheal (19% vs 14%) and bloodstream (17% vs 11%, P<.005 for both) infections and were more likely to receive transfusions (red cells 55% vs 43%; FFP 74% vs 66%; P<.009 for both). ALF-SLI patients were less likely to receive LT (18% vs 25%, P=.02) and had significantly decreased 21-day TFS (34% vs 42%) and overall survival (49% vs 64%, P<.007 for both). After adjusting for significant covariates (INR, bilirubin, acetaminophen aetiology), the development of SLI was independently associated with decreased 21-day TFS (OR 0.71, P=.03) in ALF patients (C-index 0.78). The incorporation of SLI improved discriminatory ability of the King's College Criteria (P=.0061) but not the ALFSG prognostic index (P=.34). Significant lung injury is a common complication in ALF patients that adversely affects patient outcomes.

The association between FABP7 serum levels with survival and neurological complications in acetaminophen-induced acute liver failure: a nested case\u2013control study

BackgroundAcetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality due to intracranial hypertension (ICH), a result of cerebral edema (CE) and astrocyte swelling. Brain-type fatty acid-binding protein (FABP7) is a small (15 kDa) cytoplasmic protein abundantly expressed in astrocytes. The aim of this study was to determine whether serum FABP7 levels early (day 1) or late (days 3–5) level were associated with 21-day mortality and/or the presence of ICH/CE in APAP-ALF patients.MethodsSerum samples from 198 APAP-ALF patients (nested case–control study with 99 survivors and 99 non-survivors) were analyzed by ELISA methods and assessed with clinical data from the US Acute Liver Failure Study Group (ALFSG) Registry (1998–2014).ResultsAPAP-ALF survivors had significantly lower serum FABP7 levels on admission (147.9 vs. 316.5 ng/ml, p = 0.0002) and late (87.3 vs. 286.2 ng/ml, p < 0.0001) compared with non-survivors. However, a significant association between 21-day mortality and increased serum FABP7 early [log FABP7 odds ratio (OR) 1.16, p = 0.32] and late (log FABP7 ~ OR 1.34, p = 0.21) was not detected after adjusting for significant covariates (MELD, vasopressor use). Areas under the receiver-operating curve for early and late multivariable models were 0.760 and 0.892, respectively. In a second analysis, patients were grouped based on the presence (n = 46) or absence (n = 104) of ICH/CE. A significant difference in FABP7 levels between patients with or without ICH/CE at early (259.7 vs. 228.2 ng/ml, p = 0.61) and late (223.8 vs. 192.0 ng/ml, p = 0.19) time points was not identified.ConclusionSerum FABP7 levels were significantly elevated at early and late time points in APAP-ALF non-survivors compared to survivors. However, significant differences in FABP7 levels by 21-day mortality were not ascertained after adjusting for significant covariates (reflecting severity of illness). Our study suggests that FABP7 may not discriminate between patients with or without intracranial complications.

Determinants of outcome among patients with acute liver failure listed for liver transplantation in the United States.

Analyses of outcomes after acute liver failure (ALF) have typically included all ALF patients regardless of whether they were listed for liver transplantation (LT). We hypothesized that limiting analysis to listed patients might provide novel insights into factors associated with outcome, focusing attention on disease evolution after listing. Listed adult ALF patients enrolled in the US Acute Liver Failure Study Group registry between 2000 and 2013 were analyzed to determine baseline factors associated with 21-day outcomes after listing. We classified 617 patients (36% of overall ALF group) by 3-week outcome after study admission: 117 were spontaneous survivors (SSs; survival without LT), 108 died without LT, and 392 underwent LT. Only 22% of N-acetyl-p-aminophenol (APAP) ALF patients were listed; however, this group of 173 patients demonstrated greater illness severity: higher coma grades and more patients requiring ventilator, vasopressor, or renal replacement therapy support. Only 62/173 (36%) of APAP patients received a graft versus 66% for drug-induced liver injury patients, 86% for autoimmune-related ALF, and 71% for hepatitis B-related ALF. APAP patients were more likely to die than non-APAP patients (24% versus 17%), and the median time to death was sooner (2 versus 4.5 days). Despite greater severity of illness, the listed APAP group still had a SS rate of 40% versus 11% for non-APAP causes (P < 0.001). APAP outcomes evolve rapidly, mainly to SS or death. Patients with APAP ALF listed for LT had the highest death rate of any etiology, whereas more slowly evolving etiologies yielded higher LT rates and, consequently, fewer deaths. Decisions to list and transplant must be made early in all ALF patients, particularly in those with APAP ALF.

Plasma osteopontin in acute liver failure

BackgroundOsteopontin (OPN) is a novel phosphoglycoprotein expressed in Kupffer cells that plays a pivotal role in activating natural killer cells, neutrophils and macrophages. Measuring plasma OPN levels in patients with acute liver failure (ALF) might provide insights into OPN function in the setting of massive hepatocyte injury. MethodsOPN levels were measured using a Quantikine® ELISA assay on plasma from 105 consecutive ALF patients enrolled by the US Acute Liver Failure Study Group, as well as controls including 40 with rheumatoid arthritis (RA) and 35 healthy subjects both before, and 1 and 3days after undergoing spine fusion (SF) surgery as a model for acute inflammation. ResultsMedian plasma OPN levels across all etiologies of ALF patients were elevated 10- to 30-fold: overall median 1055ng/mL; range: 33–19,127), when compared to healthy controls (median in pre-SF patients: 41ng/mL; range 2.6–86.4). RA and SF post op patients had elevated OPN levels (37ng/mL and 198ng/mL respectively), well below those of the ALF patients. Median OPN levels were highest in acetaminophen (3603ng/mL) and ischemia-related ALF (4102ng/mL) as opposed to viral hepatitis (706ng/mL), drug-induced liver injury (353ng/mL) or autoimmune hepatitis (436ng/mL), correlating with the degree of hepatocellular damage, as reflected by aminotransferase values (R value: 0.47 for AST, p<0.001). ConclusionsOPN levels appeared to correlate with degree of liver necrosis in ALF. Very high levels were associated with hyperacute injury and good outcomes. Whether OPN exerts a protective effect in limiting disease progression in this setting remains uncertain.

Therapeutic hypothermia in acute liver failure: a multicenter retrospective cohort analysis.

The benefit of therapeutic hypothermia (TH) in acute liver failure (ALF) has not been previously demonstrated in a controlled fashion. This study sought to determine the impact of TH on 21-day survival and complications in ALF patients at high risk for cerebral edema. This was a retrospective cohort study of ALF patients in the US Acute Liver Failure Study Group with grade III or IV hepatic encephalopathy. TH (32°C-35°C) was used in 97 patients (8%); 1135 (92%) who were not cooled were controls. Intracranial pressure was monitored in 38 TH ALF patients (39.2% versus 22% of controls, P < 0.001). Rates of bleeding (12% for both) and bloodstream (17% versus 18%) and tracheal infections (21% versus 23%, P > 0.5 for all) were similar. Unadjusted 21-day overall (62% versus 60%) and transplant-free survival rates (45% versus 39%, P > 0.4 for both) were similar. Multivariate models were created for acetaminophen (APAP) patients (n = 582) and non-APAP patients (n = 613). For APAP patients, the Model for End-Stage Liver Disease [MELD; odds ratio (OR) = 0.91 per increment, 95% confidence interval (CI) = 0.89-0.94, P < 0.001] and vasopressors (OR = 0.16, 95% CI = 0.11-0.24, P < 0.001) were associated with decreased 21-day spontaneous survival. Survival was improved with TH in APAP patients who were <25 years old (age of 25 years: OR = 2.735, 95% CI = 1.001-7.467) but worsened for APAP patients who were 64 years old or older (age of 64 years: OR = 0.167, 95% CI = 0.028-0.999). For non-APAP patients, MELD (OR = 0.93 per increment, 95% CI = 0.91-0.95, P < 0.001) and vasopressors (OR = 0.60, 95% CI = 0.40-0.90, P = 0.01) were associated with worse outcomes, whereas TH had no impact (P = 0.93). In conclusion, TH in ALF was not associated with increased bleeding or infections. Although young APAP ALF patients may benefit, TH did not consistently affect 21-day survival. A prospective trial is required to clarify the utility of TH in ALF patients.

Circulating mannan-binding lectin, M-, L-, H-ficolin and collectin-liver-1 levels in patients with acute liver failure.

The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL), M-, L-, and H-ficolin and collectin-liver-1 (CL-L1), which are predominantly synthesized in the liver. We aimed to study lectin levels in ALF patients and associations with clinical outcome. Serum samples from 75 patients enrolled by the US ALF Study Group were collected on days 1 and 3. We included 75 healthy blood donors and 20 cirrhosis patients as controls. Analyses were performed using sandwich-type immunoassays (ELISA, TRIFMA). At day 1, the MBL level in ALF patients was 40% lower compared with healthy controls {[median (interquartile range) 0.72 μg/ml(0.91) vs. 1.15 (1.92)(P = 0.02]}, and increased significantly by day 3 [0.83 μg/ml(0.94)(P = 0.01)]. The M-ficolin level was 60% lower [0.54 μg/ml(0.50) vs. 1.48(1.01)(P < 0.0001)]. The CL-L1 level at day 1 was slightly higher compared with healthy controls [3.20 μg/ml(2.37) vs. 2.64(0.72)(P = 0.11)]; this was significant at day 3 [3.35(1.84)(P = 0.006)]. H- and L-ficolin levels were similar to healthy controls. Spontaneous ALF survivors had higher levels of MBL at day 1 [0.96 μg/ml(1.15) vs. 0.60(0.60)(P = 0.02)] and lower levels of L-ficolin by day 3 compared with patients who died or were transplanted [1.61 μg/ml(1.19) vs. 2.17(2.19)(P = 0.02)]. We observed significant dynamics in lectin levels in ALF patients, which may suggest they play a role in ALF pathogenesis. High MBL and low L-ficolin levels are associated with survival.

Effects of Antimicrobial Prophylaxis and Blood Stream Infections in Patients With Acute Liver Failure: A Retrospective Cohort Study

We investigated whether antimicrobial prophylaxis alters the incidence of bloodstream infection in patients with acute liver failure (ALF), and whether bloodstream infections affect overall mortality within 21 days after development of ALF. We performed a retrospective cohort analysis of 1551 patients with ALF enrolled by the US Acute Liver Failure Study Group from January 1998 through November 2009. We analyzed data on infections in the first 7 days after admission and the effects of prophylaxis with antimicrobial drugs on the development of bloodstream infections and 21-day mortality. In our study population, 600 patients (39%) received antimicrobial prophylaxis and 226 patients (14.6%) developed at least 1 bloodstream infection. Exposure to antimicrobial drugs did not affect the proportion of patients who developed bloodstream infections (12.8% in patients with prophylaxis vs 15.7% in nonprophylaxed patients; P= .12), but a greater percentage of patients who received prophylaxis received liver transplants (28% vs 22%; P= .01). After adjusting for confounding factors, overall mortality within 21 days was associated independently with age (odds ratio [OR], 1.014), Model for End-stage Liver Disease score at admission (OR, 1.078), and vasopressor administration at admission (OR, 2.499). Low grade of coma (OR, 0.47) and liver transplantation (OR, 0.101) reduced mortality. Although bloodstream infection was associated significantly with 21-day mortality (P= .004), an interaction between bloodstream infection and etiology was detected: blood stream infection affected mortality to a greater extent in nonacetaminophen ALF patients (OR, 2.03) than in acetaminophen ALF patients (OR, 1.14). Based on a large, observational study, antimicrobial prophylaxis does not reduce the incidence of bloodstream infection or mortality within 21 days of ALF. However, bloodstream infections were associated with increased 21-day mortality in patients with ALF-to a greater extent in patients without than with acetaminophen-associated ALF. Our findings do not support the routine use of antimicrobial prophylaxis in patients with ALF.

Epstein–Barr Virus (EBV) Related Acute Liver Failure: A Case Series from the US Acute Liver Failure Study Group

Acute liver failure (ALF) is a rare clinical syndrome associated with a high case fatality rate. Asymptomatic primary infection with Epstein-Barr virus (EBV) is common in the general population while acute hepatitis and jaundice are much less common and ALF has been rarely reported. We reviewed the presenting features as well as clinical outcomes amongst consecutive adults with EBV-related ALF. Amongst the 1,887 adult ALF patients enrolled into the US ALF Study Group from January 1998 to February 2012, there were four patients (0.21 %) with EBV-related ALF. Diagnostic criteria for acute EBV infection included compatible serologies and/or the detection of EBV-encoded RNA (EBER) in liver tissue. Median patient age was 30 years (range 18-44); 75 % were male, and only 25 % were immunosuppressed. The median presenting ALT was 504 IU/mL (range 156-4,920), median Alk P was 431 (range 136-1,009), and median bilirubin was 17 mg/dL (range 13-22.1). Liver biopsy findings ranged from cholestasis to submassive necrosis with EBER + staining in two of the three samples tested. Although all of the patients were treated with an antiviral agent, two died of ALF, one underwent liver transplantation (LT) and one survived with supportive care and is well at 5 years. A review of the literature identified four additional LT recipients with favorable long-term outcomes. Primary EBV infection accounts for <1 % of consecutive adult ALF cases but is associated with a high case fatality rate. LT is associated with favorable short- and long-term outcomes.

A multicenter retrospective cohort analysis of therapeutic hypothermia in acute liver failure

Cerebral edema is a severe and life-threatening complication in acute liver failure (ALF). Concerns exist that therapeutic hypothermia (TH) may increase the risk of infection, worsen coagulopathy and inhibit hepatic regeneration. We therefore reviewed the experience in use of TH in participating US Acute Liver Failure Study Group (ALFSG) centers. The aims were to determine utilization of TH in ALF patients at high risk for cerebral edema (grade III or IV hepatic encephalopathy (HE)) and to determine its effect on survival and complication rates.

Pathogenesis of Liver Injury in Acute Liver Failure

Acute liver failure (ALF) represents the most severe damage an organ can sustain and can lead to shock, coagulopathy, altered mentation, cerebral edema, renal failure, infection, and, ultimately, multiorgan failure. The US Acute Liver Failure Study Group (ALFSG; available at: acuteliverfailure.org), convened a meeting on October 17 and 18, 2011, and included clinical, translational and fundamental investigators to discuss the pathogenesis of acute hepatocyte injury, how it occurs, and its downstream effects. The ALFSG has, for the past 14 years, carefully collected detailed clinical information and bio-samples from roughly 2000 patients with ALF at 24 tertiary medical centers across the United States. This meeting sought to summarize our current understanding of the pathogenetic factors that drive acute liver injury. These included consideration of (1) the contribution of innate immunity to liver injury, (2) the role of cytokine release in perpetuating liver injury and causing multiorgan failure, (3) mechanisms of apoptosis in ALF, (4) alterations in signal transduction with a focus on the role of c-Jun N-terminal kinase (JNK), (5) the contribution of infection to the pathogenesis of ALF, (6) the emerging centrality of inflammasome and sterile inflammation in the pathogenesis of ALF, (7) systems biology approaches to integrating and ordering the wide array of seemingly massively perturbed effectors in ALF, (8) host genetics and its contribution to ALF susceptibility, including a consideration of the power of next generation sequencing tools as they relate to ALF, and (9) contribution of liver regeneration to counteraction of ALF. Finally, we considered novel therapeutic strategies for ALF based on these pathogenetic concepts.

Use of Nucleoside (Tide) Analogues in Patients with Hepatitis B-Related Acute Liver Failure

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF. The US Acute Liver Failure Study Group, a 23-site registry, prospectively enrolled 1,413 patients with ALF with different etiologies between 1998 and 2008. Of those, 105 patients were identified as HBV-ALF patients, of whom we excluded those without data on NA use or with co-infection with hepatitis C, leaving 85 patients, 43 of whom had received NA treatment. HBV-DNA on admission was quantified by real time polymerase chain reaction. The treated and untreated groups were similar in most respects but differed significantly in regard to higher aminotransferase and bilirubin levels and hepatic coma grades, all being observed in the untreated group. Median duration of NA treatment was 6 days (range, 1-21 days). Overall survival in the NA treated and untreated groups were 61 and 64%, respectively (P=0.72). Rates of transplant-free survival were 21 and 36% in the treated and untreated groups, respectively (P=0.42). Multivariate analysis revealed that not using a NA [odds ratio (OR) 4.4, 95% CI 1.1-18.1, P=0.041], hepatic coma grade I or II [OR 14.4, 95% CI 3.3-62.8, P<0.001] and prothrombin time (PT) [OR 0.59, 95% CI 0.39-0.89, P=0.012] were predictors of improved transplant-free survival. Patients who are admitted with established HBV-ALF do not appear to benefit from viral suppression using nucleoside(tide) analogues presumably because of rapid disease evolution and short treatment duration. Despite the lack of benefit, NAs should still be given to transplantation candidates since viral suppression prevents recurrence after grafting.

Autoimmune acute liver failure

We read with great interest the article entitled “Autoimmune Acute Liver Failure: Proposed Clinical and Histological Criteria” by Stravitz et al.1 Our reading of this article has given rise to several comments. It is necessary to be very cautious when one is ranking histological features first in the diagnosis and management of severe forms of autoimmune disease; during their study, Stravitz et al.1 examined liver biopsy samples from 72 of 204 patients (i.e., 35% of the total cohort). However, the use of different liver biopsy techniques, such as transjugular liver biopsy, native liver biopsy, and postmortem biopsy, may have induced variations in the histological patterns. Centrilobular necrosis (CN), which corresponds to massive hepatic necrosis type 1 in this study, is an important but infrequent histopathological pattern of autoimmune hepatitis; centrilobular necrosis with sparing of the portal tracts was present in 3.5% of the cases reported by Hofer et al.2 This particular pattern is of crucial importance because it may be indicative of an early stage of the disease. For the series described by Stravitz et al., it would be interesting to have a description of the phenotype and, more specifically, the prognosis of the patients with isolated centrilobular necrosis. The fact that the centrilobular zone is damaged during an early stage by the immune process is intriguing and suggests that specific autoantigens in this area could be presented to the immune system early during the course of liver disease. Clearly, the identification of these potential targets during an initial phase of the disease would be of considerable interest. In addition, it is unfortunate that the identification of a pattern typical of severe autoimmune hepatitis (AIH) is based only on this experience; in several reports, researchers have attempted to describe this entity, and experiences besides those of the US Acute Liver Failure Study Group should be cited.3-6 In particular, the characteristics of the patients may differ between the studies. In our cohort, 8 of 16 patients (50%) suffered from grade 3/4 encephalopathy,3 whereas 26 of 72 patients (39%) in Stravitz et al.'s study did. The most important and problematic issue in the management of severe autoimmune liver disease is corticosteroid therapy. Of course, if a response to corticosteroid therapy is an important argument in favor of an autoimmune process, it is important that any decision to administer this therapy be balanced against the high potential risk of sepsis; infections occurred in 5 of 12 patients (42%) during steroid therapy in our study.3 If treatment failure seems to be predicted by changes in the Model for End-Stage Liver Disease–Sodium score and the UK Model for End-Stage Liver Disease score on day 7,7 specific scores on entry must be defined for making decisions about the administration of steroid therapy. Jean-Charles Duclos-Vallée M.D., Ph.D.* , Philippe Ichai M.D.* , Didier Samuel M.D., Ph.D.* , * Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique–Hôpitaux de Paris, Villejuif, France, Unités Mixtes de Recherche en Santé 785, Université Paris-Sud, Villejuif, France, Unité 785, Institut National de la Santé et de la Recherche Médicale, Villejuif, France.

Drug-induced liver injury: a summary of recent advances

Introduction: The knowledge base of drug-induced liver injury (DILI) continues to grow each year as additional drugs are identified as hepatotoxins. There is still a need to improve our ability to predict and diagnose DILI in the preclinical and post-approval settings.Areas covered: This article presents the new and updated DILI registries for 2010, including the latest information on the causes and outcomes of non-acetaminophen DILI cases in the US Acute Liver Failure Study Group database. As DILI is still largely a diagnosis of exclusion, it is appropriate that causality assessment instruments are again the subject of considerable discussion.Expert opinion: DILI research remains extremely active including studies aimed at being better able to identify causative agents, utilize potential biomarkers, predict who is at greatest risk of injury and manage outcomes. With respect to identifying DILI risk factors at the genetic level, the field is rapidly approaching the day where ‘personalized medicine’ (based on pharmacogenomics) will become a reality. A large single-center series from India reminds us that geography can influence the drugs responsible for liver injury; however, Hy's law remains universal. As our DILI knowledge continues to grow, it remains essential to keep abreast of the important changes reported each year.

Focus

Focus

Outcome of acute liver failure in the elderly

Older age is considered a poor prognostic factor in acute liver failure (ALF) and may still be considered a relative contraindication for liver transplantation for ALF. We aimed to evaluate the impact of older age, defined as age > or = 60 years, on outcomes in patients with ALF. One thousand one hundred twenty-six consecutive prospective patients from the US Acute Liver Failure Study Group registry were studied. The median age was 38 years (range, 15-81 years). One thousand sixteen patients (90.2%) were younger than 60 years (group 1), and 499 (49.1%) of these had acetaminophen-induced ALF; this rate of acetaminophen-induced ALF was significantly higher than that in patients > or = 60 years (group 2; n = 110; 23.6% with acetaminophen-induced ALF, P < 0.001). The overall survival rate was 72.7% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 67.9% in group 1 and 48.2% in group 2 for non-acetaminophen patients (P < 0.001). The spontaneous survival rate (ie, survival without liver transplantation) was 64.9% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 30.8% in group 1 and 24.7% in group 2 for non-acetaminophen patients (P = 0.27). Age was not a significant predictor of spontaneous survival in multiple logistic regression analyses. Group 2 patients were listed for liver transplantation significantly less than group 1 patients. Age was listed as a contraindication for transplantation in 5 patients. In conclusion, in contrast to previous studies, we have demonstrated a relatively good spontaneous survival rate for older patients with ALF when it is corrected for etiology. However, overall survival was better for younger non-acetaminophen patients. Fewer older patients were listed for transplantation.

Acetaminophen‐related acute liver failure in the United States

Acetaminophen overdoses are the number one cause of acute liver failure (ALF) in the United States; they account for 50% of all cases of ALF and carry a 30% mortality. Nevertheless, acetaminophen is a highly successful product with sales easily exceeding a billion dollars annually. A narcotic-containing acetaminophen preparation is the number one generic drug sold in the United States. Historically, a strong association was claimed with alcohol as a co-factor and the accidental nature of ingestions was emphasized but the association with alcohol remains a matter of debate. Recently, a very reliable assay has been developed which detects a byproduct of the toxic reaction, acetaminophen-CYS adducts, protein-acetaminophen compounds that are released from damaged hepatocytes in similar fashion to aminotransferases. The US Acute Liver Failure Study Group is a multi-center network established to gather data prospectively on all forms of acute liver failure, a rare but often fatal condition. The group has data on more than 500 acetaminophen cases and described 275 of them in detail in a recent paper. The clinical pattern of presentation is somewhat different in the US compared with the UK, since nearly half are considered to be unintentional, the result of overuse of acetaminophen-containing compounds for pain relief, without suicidal intent. Despite the relatively good prognosis for acetaminophen overdoses, 30% die once acute liver failure occurs and this is the largest cause of death in the entire ALF registry.