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Concept: Acute liver failure

165

Trimethoprim-sulfamethoxazole (TMP-SMZ) is a commonly used antibiotic that has been associated with drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome is characterised by fever, rash, lymphadenopathy, eosinophilia and one or more major organ involvement. Although rare, TMP-SMZ is a recognised cause of fulminant hepatic failure. We report a case of a 17-year-old Chinese, male adolescent who presented with fever, myalgia, generalised maculopapular rash and lymphadenopathy after taking TMPSMZ for acne vulgaris. He subsequently developed hepatic encephalopathy and was worked up for urgent liver transplantation. He responded well to extracorporeal liver dialysis (originally intended as a bridging therapy) and subsequently recovered without the need for liver transplantation. This case report highlights the importance of early recognition of TMPSMZ-induced DRESS syndrome and the need for early discontinuation of the drug in the affected patient. Extracorporeal liver dialysis and transplantation should be considered in the management of TMP-SMZ-induced fulminant hepatic failure.

Concepts: Medical terms, Cirrhosis, Liver, Hepatology, Liver transplantation, Hepatic encephalopathy, Liver dialysis, Acute liver failure

138

Liver failure, whether arising directly from acute liver failure or from decompensated chronic liver disease is an increasing problem worldwide and results in many deaths. In the UK only 10% of individuals requiring a liver transplant receive one. Thus the need for alternative treatments is paramount. A BioArtificial Liver machine could temporarily replace the functions of the liver, buying time for the patient’s liver to repair and regenerate. We have designed, implemented and tested a clinical-scale BioArtificial Liver machine containing a biomass derived from a hepatoblastoma cell-line cultured as three dimensional organoids, using a fluidised bed bioreactor, together with single-use bioprocessing equipment, with complete control of nutrient provision with feedback BioXpert recipe processes, and yielding good phenotypic liver functions. The methodology has been designed to meet specifications for GMP production, required for manufacture of advanced therapy medicinal products (ATMPs). In a porcine model of severe liver failure, damage was assured in all animals by surgical ischaemia in pigs with human sized livers (1.2-1.6 kg liver weights). The BioArtificial liver (UCLBAL) improved important prognostic clinical liver-related parameters, eg, a significant improvement in coagulation, reduction in vasopressor requirements, improvement in blood pH and in parameters of intracranial pressure (ICP) and oxygenation.

Concepts: Blood, Intracranial pressure, Liver, Liver function tests, Hepatology, Liver disease, Liver dialysis, Acute liver failure

23

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and decades of intense study of its pathogenesis resulted in development of the antidote Nacetylcysteine, which facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. However, the narrow therapeutic window of this intervention necessitates a better understanding of the intricacies of APAP-induced liver injury for development of additional therapeutic approaches which can benefit late presenting patients. More recent investigations into APAP hepatotoxicity have established the critical role of mitochondrial dysfunction in mediating liver injury as well as clarified mechanisms of APAP-induced hepatocyte cell death. Thus it is now established that mitochondrial oxidative and nitrosative stress is a key mechanistic feature involved in downstream signaling after APAP overdose. The identification of specific mediators of necrotic cell death further establishes the regulated nature of APAP-induced hepatocyte cell death. In addition, the discovery of the role of mitochondrial dynamics and autophagy in APAPinduced liver injury provide additional insight into the elaborate cell signaling mechanisms involved in pathogenesis of this important clinical problem. In spite of these new insights into mechanisms of liver injury, significant controversy still exists on the role of innate immunity in APAP-induced hepatotoxicity.

Concepts: Immune system, Mitochondrion, Organelle, Liver, Toxicology, Paracetamol, Paracetamol toxicity, Acute liver failure

6

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n=129), we measured microRNA-122 (miR-122; high liver specificity), High Mobility Group Box-1 (HMGB1; marker of necrosis), full length and caspase-cleaved Keratin-18 (K18; markers of necrosis and apoptosis) and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and international normalised ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1 and necrosis K18 identified the development of liver injury (n=15) or not (n=84) with a high degree of accuracy and significantly outperformed ALT, INR and plasma acetaminophen concentration for the prediction of subsequently ALI (n=11) compared with no ALI (n=52) in patients presenting within 8 hours of overdose. CONCLUSION: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient individualized treatment strategies. (HEPATOLOGY 2013.).

Concepts: Patient, Hospital, Liver function tests, Hepatology, Paracetamol, Hepatitis C, Hepatotoxicity, Acute liver failure

2

Acute liver failure (ALF) may result in elevated intracranial pressure (ICP). While invasive ICP monitoring (IICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage (ICH). Contemporary ICP monitoring techniques and coagulopathy reversal strategies may be associated with a lower risk of hemorrhage. Our objective was to evaluate the safety, feasibility, impact on clinical management and outcomes associated with protocol-directed use of IICPM in ALF.

Concepts: Intracranial pressure, Liver, Management, Cerebral hemorrhage, Intracranial hemorrhage, Hepatic encephalopathy, Acute liver failure

2

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. Liver Transpl, 2013. © 2013 AASLD.

Concepts: Intracranial pressure, Liver, Hepatology, Paracetamol, Mental disorder, Nursing, Psychiatry, Acute liver failure

1

Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Here we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP.

Concepts: Liver, Hepatology, Paracetamol, Anabolic steroid, Hepatotoxicity, Acute liver failure

1

Acetaminophen toxicity is common and is characterized by hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require hepatic transplant. While there are various criteria to predict patients who might benefit from transplant, the King’s College criteria remain one of the most widely used. However, the King’s College criteria have several limitations and do not incorporate glucose, an important marker of hepatic function.

Concepts: Medicine, Liver, Therapy, Glycogen, Toxicology, Paracetamol, Gluconeogenesis, Acute liver failure

0

Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the US. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild-type (Nampt+/+)-, heterozygous knockout (Nampt+/-)-, and overexpression (NamptOE)-mice were treated with overdose of acetaminophen, followed by histological, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen-induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, whereas the effects in NamptOE mice were least severe relative to Nampt+/+ mice. Treatment of P7C3-A20, a small chemical molecule up-regulator of Nampt, ameliorated acetaminophen-induced mouse ALI over the reagent control. These findings support the fact that NAMPT protects against acetaminophen-induced ALI.

Concepts: DNA, Gene, Gene expression, Liver, Chemistry, Paracetamol, Paracetamol toxicity, Acute liver failure

0

p53 is the major cellular gatekeeper involved in proliferation, cell death, migration, and homeostasis. The role of p53 in pathogenesis of drug-induced liver injury is unknown. We investigated the role of p53 in liver injury and regeneration after acetaminophen (APAP) overdose, the most common cause of acute liver failure in the Western world. Eight-week-old male WT and p53KO mice were treated with 300mg/kg APAP (APAP300) and the dynamics of liver injury and regeneration were studied over time course of 0 to 96 hours. Deletion of p53 resulted in a 3-fold higher liver injury than WT mice. Interestingly, despite higher liver injury p53KO mice recovered similarly as the WT mice due to faster liver regeneration. Deletion of p53 did not affect APAP bioactivation and initiation of injury. Microarray analysis revealed that p53KO mice had disrupted metabolic homeostasis as well as induced inflammatory and proliferative signaling. p53KO mice showed prolonged steatosis correlating with prolonged liver injury. Initiation of liver regeneration in p53KO mice was delayed but once initiated, cell cycle was significantly faster than WT mice due to sustained AKT, ERK, and mTOR signaling. These studies show that p53 plays a pleotropic role after APAP overdose where it prevents progression of liver injury by maintaining metabolic homeostasis and also regulates initiation of liver regeneration through proliferative signaling.

Concepts: Apoptosis, Liver, Paracetamol, Homeostasis, Western world, Paracetamol toxicity, Hepatotoxicity, Acute liver failure