Acute Liver Failure Publications (16103)


Acute Liver Failure Publications

J. Hepatol.
J Hepatol 2017 Jan 11. Epub 2017 Jan 11.
Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement et Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Structure Fédérative BioSit UMS3480 CNRS-US18 Inserm, F-35043 Rennes, France. Electronic address:

The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of Pathogen Associated Molecular Patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the Receptor Interacting Protein Kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis. Read More

Hepatitis was induced in mice by independent injections of two different bacterial PAMPs: lipopolysaccharide (LPS) and unmethylated CpG oligodeoxynucleotide (CpG-DNA) motifs. The role of RIPK1 was evaluated by making use of mice specifically lacking RIPK1 in liver parenchymal cells (Ripk1(LPC-KO)). Administration of clodronate encapusated-liposome served to investigate the role of Kupffer cells in the establishment of the disease. Etanercept, a Tumor Necrosis Factor (TNF)-decoy receptor, was used to study the contribution of TNF-α during LPS-mediated liver injury.
Whereas RIPK1 deficiency in liver parenchymal cells did not trigger basal hepatolysis, it greatly sensitized hepatocyte to apoptosis and to liver damages following single injection of LPS or CpG-DNA. Importantly, hepatocyte death was prevented by previous macrophage depletion or by TNF inhibition.
Our data highlight the pivotal function of RIPK1 in maintaining liver homeostasis in conditions of macrophage-induced TNF burst in response to PAMPs sensing.
An excessive hepatocyte death is a characteristic of liver injury. A new programmed cell death pathway has been described involving upstream death ligands such as TNF and downstream kinases such as RIPK1. Here, we show that in the presence of LPS in liver induced hepatic injury due to secreted of TNF by liver macrophages and that RIPK1 is a powerful protector of hepatocyte death. This newly identified pathway in liver may therefore be helpful in the management of patients in the prediction of their risk to develop acute liver failure.

Concurrent to development of more effective drugs for treatment of hepatitis C virus (HCV), infection, there has been an increase in the incidence of non-alcoholic fatty liver disease (NAFLD). Data indicate that liver transplantation prolongs survival times of patient with acute hepatitis associated with alcoholic liver disease (ALD). We compared data on disease prevalence in the population with data from liver transplantation waitlists to evaluate changes in the burden of liver disease in the United States. Read More

We collected data on the prevalence of HCV from the National Health and Nutrition Examination Survey (NHANES), from the 2010 and 2013-2014 cycles. We also collected data from the HealthCore Integrated Research Database on patients with cirrhosis and chronic liver failure (CLF) from 2006 through 2014, and data on patients who received transplant from the United Network for Organ Sharing (UNOS), from 2003 through 2015. We determined percentages of new waitlist members and transplant recipients with HCV infection, stratified by indication for transplant, modeling each calendar year as a continuous variable using the Spearman rank correlation, non-parametric test of trends, and linear regression models.
In an analysis of data from the NHANES (2013-2014), we found that the proportion of patients with a positive HCV antibody who had a positive HCV RNA was 0.5 (95% CI, 0.42-0.55); this value was significantly lower than in 2010 (0.64; 95% CI, 0.59-0.73) (P=.03). Data from the HealthCore databased revealed significant changes (P<.05 for all), over time, in percentages of patients with compensated cirrhosis (decreases in percentages of patients with cirrhosis from HCV or ALD, but increase in percentages of patients with cirrhosis from non-alcoholic steatohepatitis [NASH]), CLF (decreases in percentages of patients with CLF from HCV or ALD, with an almost 3-fold increase in percentage of patients with CLF from NASH), and hepatocellular carcinoma (HCC) (decreases in percentages of patients with HCC from HCV or ALD and a small increase in HCC among persons with NASH). Data from the UNOS revealed that among patients new to the liver transplant waitlist, or undergoing liver transplantation, for CLF, there was a significant decrease in the percentage with HCV infection and increases in percentages of patients with NAFLD or ALD. Among patients new to the liver transplant waitlist, or undergoing liver transplantation, for HCC, proportions of those with HCV infection, NAFLD, or ALD did not change between 2003 and 2015 CONCLUSIONS: In an analysis of 3 different databases (NHANES, HealthCore, and UNOS), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing, and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis.

J. Pediatr.
J Pediatr 2017 Jan 12. Epub 2017 Jan 12.
Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.

To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P  ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days.
Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. Read More

Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days.
A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. NCT00986648.

Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis.
This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Read More

Thirty healthy subjects served as control group.
Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow-up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end-stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831±0.043vs. 0.763±0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF.
The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF.

Am. J. Chin. Med.
Am J Chin Med 2017 Jan 13:1-17. Epub 2017 Jan 13.
* Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. Read More

The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

Eur J Gastroenterol Hepatol
Eur J Gastroenterol Hepatol 2017 Jan 10. Epub 2017 Jan 10.
aDepartment of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands bData Management Center, Hospital Clinic de Barcelona, Barcelona, Spain cLiver Unit, Hospital Clínic de Barcelona, Barcelona, Spain dLiver Unit, Hospital Vall d'Hebron Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain eLiver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK fDepartment of Gastroenterology-Hepatology, St Vincent's University Hospital, Dublin, Ireland gInternal Medicine, Medical University of Graz, Graz, Austria.

Vasopressin receptor-mediated vasoconstriction is considered to be involved in the pathogenesis of organ failure in acute-on-chronic liver failure (ACLF).
We studied the association between six single nucleotide polymorphisms (SNPs) of the vasopressin 1a receptor gene and the development of organ failure in 826 patients admitted for acute decompensation of liver cirrhosis (n=641) or ACLF (n=185).
No associations were found for SNPs with the presence of circulatory or renal failure. Read More

A C>T mutation in SNP rs7308855 and a T>A mutation in SNP rs7298346 showed an association with the presence of coagulation failure in the entire population (n=61, P=0.024 and 0.060, respectively) and in the subgroup of patients with ACLF (n=44, P=0.081 and 0.056, respectively).
Genetic variation in the vasopressin 1a receptor was found not to be associated with circulatory or renal failure, but with the presence of coagulation failure in patients with acute decompensation of liver cirrhosis and ACLF.

Sci Rep
Sci Rep 2017 Jan 12;7:40323. Epub 2017 Jan 12.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur-208016, UP, India.
Sci Rep
Sci Rep 2017 Jan 12;7:40111. Epub 2017 Jan 12.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.

The onset of hepatic encephalopathy (HE) in liver failure is associated with high mortality; the underlying mechanism is undecided. Here we report that in an acute liver failure model employing intraperitoneal administration of thioacetamide in Sprague-Dawley rats, diffusion weighted imaging revealed a progressive reduction in apparent diffusion coefficient in the brain stem. Diffusion tensor imaging further showed that the connectivity between nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in brain stem and rostral ventrolateral medulla (RVLM), the origin of sympathetic innervation of blood vessels, was progressively disrupted until its disappearance, coincidental with the irreversible cessation of baroreflex-mediated sympathetic vasomotor tone signifying clinically the occurrence of brain death. Read More

In addition, superoxide, nitric oxide, peroxynitrite and ammonia levels in the NTS or RVLM were elevated, alongside swelling of astroctytes. A scavenger of peroxynitrite, but not an antioxidant, delivered intracisternally reversed all these events. We conclude that nitrosative stress because of augmented peroxynitrite related to accumulation of ammonia and swelling of astrocytes in the NTS or RVLM, leading to cytotoxic edema in the brain stem and severance of the NTS-RVLM connectivity, underpins the defunct baroreflex-mediated sympathetic vasomotor tone that accounts for the high mortality associated with HE.

Aliment. Pharmacol. Ther.
Aliment Pharmacol Ther 2017 Jan 12. Epub 2017 Jan 12.
Department of Hepatology, Shanghai Public Clinical center, Fudan University, Shanghai, China.

Symptomatic Hepatitis E virus (HEV) infection occurs in few infected subjects, and the risk factors are not completely known.
To explore the risk factors for adverse clinical outcomes in acute HEV infections.
A large retrospective study was conducted. Read More

The baseline characteristics, clinical outcomes, and laboratory data of 512 acute HEV infection cases were analysed using logistic regression models.
All patients exhibited autochthonous sporadic HEV infections, and most were elderly. Their symptoms varied from asymptomatic to severe liver diseases. In all, 215 patients (42.0%) had liver failure and/or decompensation, and 45 (8.2%) patients died within 3 months. Nearly 60% of patients had underlying chronic liver diseases (CLDs), 20% were cirrhotic, and various extrahepatic underlying comorbidities were common. The logistic regression analysis revealed that underlying CLDs, especially cirrhosis, were closely associated with disease severity (OR = 8.78, P < 0.001) but not with mortality in patients with severe liver diseases. In addition to the known factors, including an old age, the male gender and CLDs, we identified pre-existing extrahepatic tumours, diabetes, and chronic respiratory and renal diseases as novel independent predictors for adverse clinical outcomes. Importantly, patients without these four extrahepatic comorbidities showed a much lower mortality rate (4.2%, P < 0.001) than patients with one (18.5%) or more comorbidities (34.5%).
Previous comorbidities, including tumours, diabetes, and chronic liver, lung and kidney diseases, were independent risk factors for adverse outcomes, especially mortality, in acute HEV infections. This study provides valuable data for improving the prevention and control of HEV infection.

J. Gastroenterol.
J Gastroenterol 2017 Jan 11. Epub 2017 Jan 11.
Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, 0208505, Japan.

Corticosteroid therapy has been commonly administered to patients with acute liver injury (ALI)/acute liver failure (ALF) in Japan to prevent the development of hepatic encephalopathy, but the appropriate timing to start corticosteroid therapy has not been determined and optimal response evaluation of the therapy has not been conducted. We prospectively investigated the optimal timing to start therapy on the established severity indication: the Japan Hepatic Encephalopathy Prediction Model (JHEPM) and prothrombin time (PT).
This prospective observational study enrolled 469 patients with ALI/ALF from 2004 to 2015. Read More

We evaluated 44 patients with ALF on high-dose corticosteroid therapy before hepatic coma development. The predictive performance for coma development was assessed using the receiver operator curve method in both PT and JHEPM probability the day before administering high-dose corticosteroid therapy.
Among these patients, nine developed hepatic coma after the therapy. Selection bias was adjusted using propensity score method. High-dose corticosteroid therapy tended to decrease the risk of coma development although there was no statistical significance. The cut-off value of 53%, 1.95, and 39% in JHEPM probability, PT-international normalized ratio (PT-INR), and PT activity, respectively, showed high sensitivity and specificity.
We propose the appropriate timing to start high-dose corticosteroid therapy in patients with ALI/ALF; 40% of JHEPM probability, 1.53 of PT-INR, and 52% of PT because these values were theoretically discriminated at 98% coverage to the patients with coma. Because the study contained selection bias, the appropriate timing for therapy should be confirmed in a future prospective study.