Acute Liver Failure Study Group Research Articles

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.

Steroid use in acute liver failure.

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores.

Akutes Leberversagen

ZusammenfassungDas akute Leberversagen (ALV) ist mit einer Prävalenz von 5 pro 1 Mio. Einwohner zwar selten, besitzt aber eine sehr hohe Mortalitätsrate von etwa 34 %. Es wird in westlichen Zivilisationen hauptsächlich durch Medikamente (Paracetamol) und virale Hepatitiden ausgelöst. Die Patienten sind hauptsächlich durch den Ausfall der Lebersynthesefunktion, die Entwicklung einer hepatischen Enzephalopathie und ein mögliches Multiorganversagen gefährdet. Spezifische Therapien sind mit der Gabe von N-Acetylcystein (Paracetamol) oder von Nukleotid-/Nukleosid-Analoga (Hepatitis-B) zwar möglich, oft aber nicht ausreichend effektiv. Die Durchführung einer Lebertransplantation ist hier oft die einzige verbleibende Therapieoption. Neue Prognosescores, wie der Acute-liver-failure-study-group(ALFSG)-Score, ermöglichen eine verbesserte Patientenselektion, um dem Organmangel durch eine ausreichend stringente Indikationsstellung gerecht zu werden.

Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure.

Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF.

Acute Liver and Multi-organ Failure Secondary to Intentional Iron Overdose

Introduction: Intentional iron overdoses are rare in adults, but have severe consequences. We report two patients with multi-organ system failure occurring rapidly after large quantity oral iron ingestions. Case Discussion: A 26-year-old woman was transferred from an outside hospital (OSH) for acute liver failure (ALF): 48 hours prior, she had intentionally ingested a large amount of iron supplements. At initial presentation, she had nausea, gastrointestinal bleeding and normal liver enzyme levels. She then developed abdominal pain, tender hepatomegaly, elevated liver enzymes and coagulopathy (see table). No asterixis or encephalopathy was present. Deferoxamine, N-acetylcysteine (NAC) and dialysis were initiated. She progressed to coma, shock, brainstem herniation and death. Case B: A 35-year-old woman with prior gastric bypass surgery, hypertension, iron deficiency anemia and previous suicide attempt was transferred from an OSH with ALF after intentionally ingesting 300 iron pills the evening before. She developed nausea, vomiting, diarrhea and abdominal pain. Initially, she was hypertensive, had a tender abdomen, but no asterixis. Acute kidney injury (AKI) and severe acidosis were managed with intravenous fluids and, eventually, dialysis. She also received a proton pump inhibitor, NAC, polyethylene glycol laxative and deferoxamine. She recovered after 16 days, with liver enzymes and INR near normal. However, she remained dialysis-dependent on discharge, and subsequently has been lost to follow-up. Acetaminophen adducts were negative, and no radio-opaque pills were identified on abdominal x-ray (KUB) in either case. Discussion: Iron overdose causes rapid onset multi-organ failure with high mortality. Iron-induced oxidative damage results from hepatocyte exposure to high quantities of non-transferrin bound iron via the portal venous system, resulting in excessive free radical production. Peak serum iron levels occur 4-6 hours after ingestion. Bowel irrigation is indicated if tablets are identified on KUB. IV deferoxamine should be administered early if systemic signs such as metabolic acidosis are present. NAC can be given empirically. AKI is thought to be from direct mitochondrial injury and lactic acidosis. In case B, survival may, in part, have been due to the history of gastric bypass surgery, which may have limited absorption. These patients were enrolled in the Acute Liver Failure Study Group registry, supported by U-01-58369-014 from NIDDK.Table 5: Liver function tests

Indocyanine green plasma disappearance rate: a new tool for the classification of paediatric patients with acute liver failure

Pediatric acute liver failure is a rare disorder which results in death or the need for liver transplantation in 25-50% of cases. The adults scores are unable to predict survival without liver transplantation of pediatric patients. The present study assessed the use the of indocyanine green plasma disappearance rate as a tool to predict the evolution of pediatric patients with acute liver failure. All patients met the criteria of acute liver failure according to the Pediatric Acute Liver Failure Study Group. King's College, Clichy's criteria and ICG-PDR were obtained on admission or when acute liver failure was diagnosed and repeated every 12-24 hours, respectively. Thirteen out of 48 patients suffered an irreversible liver damage. Seven of them underwent a liver transplantation and 6 died on the waiting. A total of 154 ICG-PDR measurements were taken during the study (Median 12.4 %/min, r:6.2 - 26.3). The ICG-PDR was significantly lower in patients who suffered irreversible liver damage compared with those who survived without liver transplantation (median ICG-PDR 4.1 %/min; r:4.0 - 5.7 vs median ICG-PDR 20.3 %/min; r: 9.1 - 30.1; respectively. P < 0.001). Using a ROC curve the cutoff of ICG-PDR for assessing the need for liver transplantation was set at 5.9 %/min (sensitivity 92.3%, specificity 97.1%). Sensitivity, specificity, PPV, NPV and DA for ICG-PDR were higher than the King's College and Clichy's criteria. ICG-PDR is a powerful tool that would improve the categorization of patients with pediatric acute liver failure.

Quality of life is significantly impaired in long-term survivors of acute liver failure and particularly in acetaminophen-overdose patients

Functional outcomes for long-term survivors of acute liver failure (ALF) are not well characterized. The aim of this prospective study was to determine health-related quality of life in long-term adult ALF survivors. Acute Liver Failure Study Group registry participants completed the Centers for Disease Control and Prevention Health-Related Quality of Life 14 and Short Form 36 (SF-36) questionnaires at 1- and/or 2-year follow-up study visits. Responses were compared among ALF subgroups and to those for available general US population controls. Among the 282 adult ALF patients, 125 had undergone liver transplantation (LT), whereas 157, including 95 acetaminophen overdose (APAP) patients and 62 non-APAP patients, were spontaneous survivors (SSs). APAP SS patients reported significantly lower general health scores and more days of impaired mental and physical health, activity limitations due to poor health, pain, depression, and anxiety in comparison with the other groups (P ≤ 0.001). There were no significant differences in coma grade or in the use of mechanical ventilation or intracranial pressure monitoring among the patient groups during their ALF hospitalization, but APAP SSs had significantly higher rates of psychiatric disease and substance abuse (P < 0.001). In comparison with the general US population, a greater proportion of the combined SS patients reported fair or poor health and ≥14 days of impaired physical/mental health and activity limitations due to poor health. In addition, a greater proportion of LT recipients reported ≥14 days of impaired physical/mental health. Similar results were observed with the SF-36 across the 3 ALF subgroups and in comparison with population controls. In conclusion, long-term adult survivors of ALF reported significantly lower quality of life scores than US population controls. Furthermore, APAP SS patients reported the lowest quality of life scores, possibly because of higher rates of premorbid psychiatric and substance abuse disorders.

Effects of N‐acetylcysteine on cytokines in non‐acetaminophen acute liver failure: potential mechanism of improvement in transplant‐free survival

N-Acetylcysteine (NAC) improves transplant-free survival in patients with non-acetaminophen acute liver failure (ALF) when administered in early stages of hepatic encephalopathy. The mechanisms of this benefit are unknown. To determine whether NAC improves transplant-free survival in ALF by ameliorating the surge of pro-inflammatory cytokines. Serum samples were obtained from 78 participants of the randomized, ALF Study Group NAC Trial with grade 1 or 2 hepatic encephalopathy on randomization. Concentrations of ten cytokines, chosen to represent a wide array of inflammatory responses, were determined by multiplex enzyme-linked immunosorbent assay ELISA. In univariate analysis, predictors of transplant-free survival included NAC administration (P=0.012), admission bilirubin (P=0.003), international normalized ratio INR (P=0.0002), grade 1 vs. grade 2 encephalopathy (P=0.006) and lower admission interleukin (IL)-17 concentrations (P=0.011). IL-17 levels were higher in patients with grade 2 vs. grade 1 encephalopathy on randomization (P=0.007) and in those who progressed to grade 3 or grade 4 encephalopathy over the following 7days (P≤0.01). Stepwise multivariate logistic regression analysis identified only NAC administration and lower IL-17 concentrations as independent predictors of transplant-free survival. In patients with detectable IL-17 concentrations on admission, 78% of those who received NAC vs. 44% of those who received placebo had undetectable levels by day 3-5 (P=0.042), and the mean decrease in IL-17 concentrations between admission and late samples was significantly greater in patients who received NAC vs. placebo (P=0.045). N-acetylcysteine (NAC) may improve transplant-free survival in patients with non-acetaminophen ALF by ameliorating the production of IL-17, which is associated with progression of hepatic encephalopathy and poor outcome.

Serum sodium based modification of the MELD does not improve prediction of outcome in acute liver failure

BackgroundAcute liver failure (ALF) is a devastating clinical syndrome with a high mortality rate. The MELD score has been implied as a prognostic tool in ALF. Hyponatremia is associated with lethal outcome in ALF. Inclusion of serum sodium (Na) into the MELD score was found to improve its predictive value in cirrhotic patients. Therefore the aim of this study was to determine whether inclusion of serum Na improves the predictive value of MELD in ALF compared to established criteria.MethodsIn a prospective single center study (11/2006–12/2010), we recruited 108 consecutive ALF patients (64% females / 36% males), who met the criteria defined by the “Acute Liver Failure Study Group Germany”. Upon admission, clinical and laboratory data were collected, King’s College Criteria (KCC), Model of End Stage Liver Disease score (MELD), and serum sodium based modifications like the MELD-Na score and the United Kingdom Model of End Stage Liver Disease score (UKELD) were calculated and area under the receiver operating characteristic curve analyses were performed regarding the prediction of spontaneous recovery (SR) or non-spontaneous recovery (NSR; death or transplantation).ResultsSerum bilirubin was of no prognostic value in ALF, and Na also failed to predict NSR in ALF. The classical MELD score was superior to sodium-based modifications and KCC.ConclusionsWe validated the prognostic value of MELD-Na and UKELD in ALF. Classic MELD score calculations performed superior to KCC in the prediction of NSR. Serum Na and Na-based modifications of MELD did not further improve its prognostic value.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial

N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.

Application of Interleukin-22 Mediates Protection in Experimental Acetaminophen-Induced Acute Liver Injury

Acetaminophen (APAP, paracetamol)-induced hepatotoxicity, although treatable by timely application of N-acetylcysteine, can be fatal. Because it is among the common causes of acute liver failure in intensive care units and in light of its gradually increasing incidence, the need for novel therapeutic strategies aimed at severe intoxication is apparent. Recently, it has been shown that IL-22, a STAT3-activating cytokine, has the capability to mediate liver protection. Herein, the protective potential of IL-22 in murine APAP-induced hepatotoxicity was assessed. Intravenous administration of prophylactic IL-22 significantly reduced serum alanine aminotransferase levels and histopathologic damage in APAP-induced liver injury, a process that coincided with increased hepatocyte proliferation invivo. Concomitant gene expression analysis revealed hepatic induction of genes prototypically up-regulated by the IL-22/STAT3 axis, among others suppressor of cytokine signaling-3, lipocalin-2, and α1-antichymotrypsin. Notably, in a translational setting of therapeutic treatment 2 hours after APAP, IL-22 supported protection in the context of suboptimal N-acetylcysteine dosing. IL-22 likewise connected to augmented hepatocyte proliferation in this experimental setting. As detected by analysis of inflammatory cytokine production, systemically applied IL-22 did not display acute immunomodulation/stimulation in otherwise untreated or endotoxemic mice. Those latter observations clearly confirm acute tolerability of systemically applied IL-22. Observations presented altogether suggest that therapeutic IL-22 administration is a conceivable tissue-protective regimen aimed at hard-to-treat patients with severe APAP-induced hepatotoxicity.

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Evaluation of the Liver Injury Unit Scoring System to Predict Survival in a Multinational Study of Pediatric Acute Liver Failure

To examine the predictive value of the Liver Injury Units (LIU) and admission values (aLIU) of bilirubin and prothrombin time and international normalized ratio scores in a large cohort from the Pediatric Acute Liver Failure (PALF) Study Group, a multinational prospective study. LIU and aLIU scores were calculated for 461 and 579 individuals, respectively, enrolled in the PALF study from 1999 to 2008. Receiver operator characteristic curves were used to evaluate the scores with respect to survival without liver transplantation (LT), death, or LT by 21 days after enrollment. At 21 days, 50.3% of participants were alive without LT, 36.2% underwent LT, and 13.4% died. The c-indices for transplant-free survival were 0.81 based on the LIU score with the international normalized ratio (95% CI, 0.78-0.85) and 0.76 based on the aLIU score (95% CI, 0.72-0.79). The LIU score predicted LT better than it predicted death (c-index for LT 0.84, c-index for death 0.76). Based on data from a large, multicenter cohort of patients with PALF, the LIU score was a better predictor of transplant-free survival than was the aLIU score. The LIU score might be a helpful, dynamic tool to predict clinical outcomes in patients with PALF.

Development of an Accurate Index for Predicting Outcomes of Patients With Acute Liver Failure

Patients with acute liver failure (ALF) have high mortality and frequently require liver transplantation (LT); few reliable prognostic markers are available. Levels of M30, a cleavage product of cytokeratin-18 caspase, are significantly increased in serum samples from patients with ALF who die or undergo LT. We developed a prognostic index for ALF based on level of M30 and commonly measured clinical variables (called the Acute Liver Failure Study Group [ALFSG] index) and compared its accuracy with that of the King's College criteria (KCC) and Model for End Stage Liver Disease (MELD). We also validated our model in an independent group of patients with ALF. Serum levels of M30 and M65 antigen (the total cytokeratin-18 fragment, a marker of apoptosis and necrosis) were measured on 3 of the first 4 days following admission of 250 patients with ALF. Logistic regression was used to determine whether the following factors, measured on day 1, were associated with LT or death: age, etiology; coma grade; international normalized ratio (INR); serum pH; body mass index; levels of creatinine, bilirubin, phosphorus, arterial ammonia, and lactate; and log(10) M30 and log(10) M65. The area under the receiver operating characteristic (AUROC) was calculated for the ALFSG and other indices. Coma grade, INR, levels of bilirubin and phosphorus, and log(10) M30 value at study entry most accurately identified patients who would require LT or die. The ALFSG index identified these patients with 85.6% sensitivity and 64.7% specificity. Based on comparison of AUROC values, the ALFSG Index (AUROC, 0.822) better identified patients most likely to require LT or die than the KCC (AUROC, 0.654) or MELD (AUROC, 0.704) (P = .0002 and P = .0010, respectively). We validated these findings in a separate group of 250 patients with ALF. The ALFSG index, a combination of clinical markers and measurements of the apoptosis biomarker M30, better predicts outcomes of patients with ALF than the KCC or MELD.

Acute liver failure in Japan: definition, classification, and prediction of the outcome.

Acute liver failure is a clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to severe impairment of liver function caused by massive or submassive liver necrosis. Viral hepatitis is the most important and frequent cause of acute liver failure in Japan. The diagnostic criteria for fulminant hepatitis, including that caused by viral infections, autoimmune hepatitis, and drug allergy induced-liver damage, were first established in 1981. Considering the discrepancies between the definition of fulminant hepatitis in Japan and the definitions of acute liver failure in the United States and Europe, the Intractable Hepato-Biliary Disease Study Group established the diagnostic criteria for “acute liver failure” for Japan in 2011, and performed a nationwide survey of patients seen in 2010 to clarify the demographic and clinical features and outcomes of these patients. According to the survey, the survival rates of patients receiving medical treatment alone were low, especially in those with hepatic encephalopathy, despite artificial liver support, consisting of plasma exchange and hemodiafiltration, being provided to almost all patients in Japan. Thus, liver transplantation is inevitable to rescue most patients with hepatic encephalopathy. The indications for liver transplantation had, until recently, been determined according to the guideline published by the Acute Liver Failure Study Group in 1996. Recently, however, the Intractable Hepato-Biliary Disease Study Group established a scoring system to predict the outcomes of acute liver failure patients. Algorithms for outcome prediction have also been developed based on data-mining analyses. These novel guidelines need further evaluation to determine their usefulness.

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.

Mo1918 Sirolimus use is Associated With Increased Risk for Cardiovascular Events Following Liver Transplantation

N-Acetylcysteine (NAC) improves transplant-free survival (TFS) in patients with non-acetaminophen (APAP) acute liver failure (ALF) when administered in early stages of hepatic encephalopathy (HE). The mechanisms of this benefit are unknown. We hypothesized that NAC may improve TFS by ameliorating the surge of pro-inflammatory cytokines leading to the systemic inflammatory response syndrome (SIRS). Objectives. To determine the effects of NAC administration on serum cytokine concentrations, and to relate cytokine concentrations to outcome, progression of HE, and the SIRS in patients with non-APAP-induced ALF. Methods. Serum samples from 90 patients from the randomized, placebo-controlled ALF Study Group NAC Trial were analyzed. Samples from 45 patients in each group were assayed, and serum cytokine concentrations were determined in multiplex SearchLight® ELISA assays by ThermoFisher. Proand anti-inflammatory cytokines representing activation of Th1 (IL2, IFNγ, TNFα), Th2 (IL-4,6,10,13), and Treg (IL-17,23) classes of T-helper cells were chosen for assay. Results. The number of SIRS components on admission was a predictor of 21 day mortality (p=0.02 by ANOVA). Predictors of TFS in univariate analysis included NAC administration (p=0.005), admission bilirubin (p<0.001), INR (p=0.085), grade 1 vs. 2 HE (p<0.02) and higher admission IL-17 concentrations (p=0.02). However, there were no differences in any serum cytokine concentrations or in SIRS in patients treated with NAC vs. placebo. Stepwise multivariable logistic analysis identified each of these factors as independent predictors of TFS (p<0.0001). IL-17 levels were higher in patients with grade 2 vs. 1 HE (p<0.01) and in those who progressed to grade 3/4 HE (p<0.02). Patterns of elevated cytokines were observed, with levels of Th1 cytokines highly related (r=0.75, p<0.0001), and levels of proand anti-inflammatory cytokines also related (eg., IL-6 and IL-10; r=0.48, p<0.001). IL-6 and IL-10 concentrations were both related to number of SIRS on admission (p<0.01 and p<0.001) and inversely related to mean arterial pressure (r=-0.35 and -0.34, respectively; p<0.001 for both). Conclusions. NAC does not improve TFS by ameliorating the surge of pro-inflammatory cytokines in patients with non-APAPinduced ALF. However, specific proand anti-inflammatory cytokine concentrations are associated with outcome, HE grade, and the SIRS. IL-17 may have an important role in HE progression and outcome.

Mo1917 Relationship of Serum Cytokine Concentrations to Outcome, Complications and N-Acetylcysteine Treatment in Patients With Non-Acetaminophen-Induced Acute Liver Failure

N-Acetylcysteine (NAC) improves transplant-free survival (TFS) in patients with non-acetaminophen (APAP) acute liver failure (ALF) when administered in early stages of hepatic encephalopathy (HE). The mechanisms of this benefit are unknown. We hypothesized that NAC may improve TFS by ameliorating the surge of pro-inflammatory cytokines leading to the systemic inflammatory response syndrome (SIRS). Objectives. To determine the effects of NAC administration on serum cytokine concentrations, and to relate cytokine concentrations to outcome, progression of HE, and the SIRS in patients with non-APAP-induced ALF. Methods. Serum samples from 90 patients from the randomized, placebo-controlled ALF Study Group NAC Trial were analyzed. Samples from 45 patients in each group were assayed, and serum cytokine concentrations were determined in multiplex SearchLight® ELISA assays by ThermoFisher. Proand anti-inflammatory cytokines representing activation of Th1 (IL2, IFNγ, TNFα), Th2 (IL-4,6,10,13), and Treg (IL-17,23) classes of T-helper cells were chosen for assay. Results. The number of SIRS components on admission was a predictor of 21 day mortality (p=0.02 by ANOVA). Predictors of TFS in univariate analysis included NAC administration (p=0.005), admission bilirubin (p<0.001), INR (p=0.085), grade 1 vs. 2 HE (p<0.02) and higher admission IL-17 concentrations (p=0.02). However, there were no differences in any serum cytokine concentrations or in SIRS in patients treated with NAC vs. placebo. Stepwise multivariable logistic analysis identified each of these factors as independent predictors of TFS (p<0.0001). IL-17 levels were higher in patients with grade 2 vs. 1 HE (p<0.01) and in those who progressed to grade 3/4 HE (p<0.02). Patterns of elevated cytokines were observed, with levels of Th1 cytokines highly related (r=0.75, p<0.0001), and levels of proand anti-inflammatory cytokines also related (eg., IL-6 and IL-10; r=0.48, p<0.001). IL-6 and IL-10 concentrations were both related to number of SIRS on admission (p<0.01 and p<0.001) and inversely related to mean arterial pressure (r=-0.35 and -0.34, respectively; p<0.001 for both). Conclusions. NAC does not improve TFS by ameliorating the surge of pro-inflammatory cytokines in patients with non-APAPinduced ALF. However, specific proand anti-inflammatory cytokine concentrations are associated with outcome, HE grade, and the SIRS. IL-17 may have an important role in HE progression and outcome.

Acute liver failure in children: 20-year experience

We aimed to determine the causes, demographic findings, clinical status, outcomes, and prognostic risk factors of patients with acute liver failure admitted to Hacettepe University Children's Hospital between October 1987-October 2006. This retrospective case study included 74 patients with acute liver failure according to the Pediatric Acute Liver Failure Study Group definition. The etiology of acute liver failure was metabolic in 26 (35.1%) and infectious in 21 (28.4%) patients. Sixteen (21.6%) patients had indeterminate causes. Wilson's disease (16/26 patients, 61.5%) was the most frequent metabolic disease, while hepatitis A (14/21 patients, 66.7%) was the most frequent infectious agent. Neurologic functions were normal in 21 (28.4%) patients. Forty-nine (66.2%) patients died and 24 (32.4%) recovered. Two patients underwent liver transplantation. The mortality rate was 82.9% for patients who were not transplanted but fulfilled King's College Hospital criteria and 45.4% for patients who were not suitable for transplantation. This difference was statistically significant (p=0.001). Total bilirubin >5.35 mg/dl, international normalized ratio (INR) >3.66 and prothrombin time >23.5 seconds were shown to be the risk factors to predict death. Metabolic and infectious etiologies were responsible for most of the acute liver failure cases. Clinical encephalopathy may not be present in children.