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Sample records for acetaminophen-induced liver failure

  1. Use of acetylcysteine for non-acetaminophen-induced acute liver failure.

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    Sales, Ibrahim; Dzierba, Amy L; Smithburger, Pamela L; Rowe, Deanna; Kane-Gill, Sandra L

    2013-01-01

    The purpose of this review was to evaluate the effectiveness of acetylcysteine in the treatment of acute liver failure not related to acetaminophen. A search of MEDLINE April 2003 through May 2012 using the Pub Med database was conducted using the keywords acetylcysteine and non-acetaminophen-induced acute liver failure or acetylcysteine and liver failure. All human case reports, case series, and research articles that discussed the use of acetylcysteine for non-acetaminophen induced liver failure were evaluated. A total of 263 articles were identified during this broad search with 11 articles included for review in this article; eight case reports, two retrospective trials, and one prospective, randomized, double-blind multicenter study. In conclusion, the data suggest marginal benefit of IV acetylcysteine in NAI-ALF with coma grades I-II; however, the routine use of acetylcysteine cannot be recommended. It may be considered in non-transplant centers while awaiting referral or when transplantation is not an option. Further studies are necessary to determine optimal dosing, duration, and criteria for patient selection.

  2. Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

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    Howie Forbes

    2010-03-01

    Full Text Available Abstract Background The development of effective therapies for acute liver failure (ALF is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein. Control pigs (n = 4 survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg, increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3. Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3 observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02 and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14 coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis

  3. Artificial liver support in pigs with acetaminophen-induced acute liver failure

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    He, Guo-Lin; Feng, Lei; Cai, Lei; Zhou, Chen-Jie; Cheng, Yuan; Jiang, Ze-Sheng; Pan, Ming-Xin; Gao, Yi

    2017-01-01

    AIM To establish a reversible porcine model of acute liver failure (ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen (APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group (n = 11), in which a treatment procedure was performed, or a control group (n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased (P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h (at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group (P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution. Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment (P < 0.05). CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system (ZHJ-3) is safe and effective for the APAP-induced porcine ALF model. PMID:28566885

  4. Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure.

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    Cooper, Sheldon C; Aldridge, Roland C; Shah, Tahir; Webb, Kerry; Nightingale, Peter; Paris, Sue; Gunson, Bridget K; Mutimer, David J; Neuberger, James M

    2009-10-01

    Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated.

  5. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study

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    Nabi, Tauseef; Nabi, Sumaiya; Rafiq, Nadeema; Shah, Altaf

    2017-01-01

    Background/Aims: Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use. Patients and Methods: A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization. Results: The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies. Conclusion: The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe. PMID:28611340

  6. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

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    Nélson R Carvalho

    Full Text Available The acute liver failure (ALF induced by acetaminophen (APAP is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe2 to the N-acetylcysteine (NAC during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg, (PhSe2 (15.6 mg/kg, NAC (1200 mg/kg, APAP+(PhSe2 or APAP+NAC, where the (PhSe2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe2. The effectiveness of (PhSe2 was similar at a lower dose than NAC. In summary, (PhSe2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

  7. Acetaminophen-induced acute liver injury in HCV transgenic mice

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    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  8. TRPM2 channels mediate acetaminophen-induced liver damage.

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    Kheradpezhouh, Ehsan; Ma, Linlin; Morphett, Arthur; Barritt, Greg J; Rychkov, Grigori Y

    2014-02-25

    Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca(2+) homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca(2+) concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca(2+) rise. Here we report that the channel responsible for Ca(2+) entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

  9. A non-hepatotropic parasite infection increases mortality in the acetaminophen-induced acute liver failure murine model: possible roles for IL-5 and IL-6

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    Marco A De León-Nava

    Full Text Available We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group. Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT levels, CYP2E1 protein, interleukin (IL- 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group, whereas only one-third of uninfected animals exposed to acetaminophen (APAP group died. Uninfected (Control group and infected (Tc group mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients.

  10. A non-hepatotropic parasite infection increases mortality in the acetaminophen-induced acute liver failure murine model: possible roles for IL-5 and IL-6

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    De León-Nava, Marco A; Álvarez-Delgado, Carolina; Donis-Maturano, Luis; Hernández-Ruiz, Joselin; Manjarrez-Reyna, Aaron N; Cruz-Avilés, Edgar; Leon-Cabrera, Sonia; Morales-Montor, Jorge; Fragoso, José M; Escobedo, Galileo

    2016-01-01

    We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps) on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group). Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT) levels, CYP2E1 protein, interleukin (IL-) 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group), whereas only one-third of uninfected animals exposed to acetaminophen (APAP group) died. Uninfected (Control group) and infected (Tc group) mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients. PMID:27812602

  11. Predicting outcome on admission and post-admission for acetaminophen-induced acute liver failure using classification and regression tree models.

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    Jaime Lynn Speiser

    Full Text Available Assessing prognosis for acetaminophen-induced acute liver failure (APAP-ALF patients often presents significant challenges. King's College (KCC has been validated on hospital admission, but little has been published on later phases of illness. We aimed to improve determinations of prognosis both at the time of and following admission for APAP-ALF using Classification and Regression Tree (CART models.CART models were applied to US ALFSG registry data to predict 21-day death or liver transplant early (on admission and post-admission (days 3-7 for 803 APAP-ALF patients enrolled 01/1998-09/2013. Accuracy in prediction of outcome (AC, sensitivity (SN, specificity (SP, and area under receiver-operating curve (AUROC were compared between 3 models: KCC (INR, creatinine, coma grade, pH, CART analysis using only KCC variables (KCC-CART and a CART model using new variables (NEW-CART.Traditional KCC yielded 69% AC, 90% SP, 27% SN, and 0.58 AUROC on admission, with similar performance post-admission. KCC-CART at admission offered predictive 66% AC, 65% SP, 67% SN, and 0.74 AUROC. Post-admission, KCC-CART had predictive 82% AC, 86% SP, 46% SN and 0.81 AUROC. NEW-CART models using MELD (Model for end stage liver disease, lactate and mechanical ventilation on admission yielded predictive 72% AC, 71% SP, 77% SN and AUROC 0.79. For later stages, NEW-CART (MELD, lactate, coma grade offered predictive AC 86%, SP 91%, SN 46%, AUROC 0.73.CARTs offer simple prognostic models for APAP-ALF patients, which have higher AUROC and SN than KCC, with similar AC and negligibly worse SP. Admission and post-admission predictions were developed.• Prognostication in acetaminophen-induced acute liver failure (APAP-ALF is challenging beyond admission • Little has been published regarding the use of King's College Criteria (KCC beyond admission and KCC has shown limited sensitivity in subsequent studies • Classification and Regression Tree (CART methodology allows the

  12. Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study.

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    Darweesh, Samar K; Ibrahim, Mona F; El-Tahawy, Mahmoud A

    2017-05-01

    Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF. In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled. NAC infusion (in empirical dose) was given as 150 mg/kg in 100 ml dextrose 5% over half an hour, then 70 mg/kg in 500 ml dextrose 5% over 4 h, then 70 mg/kg in 500 ml dextrose 5% over 16 h. Thereafter continuous infusion was administered over 24 h of 150 mg/kg in 500 ml dextrose 5% until up to two consecutive normal international normalized ratios (INRs) were obtained. Our endpoints were recovery, transplantation, or death. The primary outcome of the study was to assess reduction in mortality or liver transplantation. The secondary outcome was the evaluation of other clinical outcomes (length of ICU and hospital stays, organ system failure, and hepatic encephalopathy). The study included a total of 155 adults; the NAC group (n = 85) were given NAC between January 2011 to December 2013 and the control group (n = 70) were not given NAC and were included from files dating between 2010 and 2011. Both groups (before NAC) were comparable with regard to etiology, age, sex, smoking, presence of co-morbidities, encephalopathy, liver profile, and INR. The success rate (transplant-free survival) in the NAC group was 96.4%. While in the control group, 17 patients (23.3%) recovered and 53 (76.6%) did not recover, of these 37 (53.3%) had liver transplantation and 16 (23.3%) died (p < 0.01). The NAC group had significantly shorter hospital stays (p < 0.001), less encephalopathy (p = 0.02), and less bleeding (p < 0.01) than the control group. The control group reported a higher ICU admission (p = 0.01) rate and

  13. Elevated FABP1 serum levels are associated with poorer survival in acetaminophen-induced acute liver failure.

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    Karvellas, Constantine J; Speiser, Jaime L; Tremblay, Mélanie; Lee, William M; Rose, Christopher F

    2017-03-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Serum liver-type fatty acid binding protein (FABP1) early (day 1) or late (day 3-5) levels are associated with 21-day mortality in the absence of liver transplant. Serum samples from 198 APAP-ALF patients (nested case-control study with 99 survivors, 99 nonsurvivors) were analyzed by enzyme-linked immunosorbent assay with clinical data from the US Acute Liver Failure Study Group registry (1998-2014). APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 versus 690.8 ng/mL, P  350 ng/mL was associated with significantly higher risk of death at early (P = 0.0004) and late (P < 0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio = 1.31, P = 0.027) and late (log FABP1 odds ratio = 1.50, P = 0.005) were associated with significantly increased 21-day mortality after adjusting for significant covariates (Model for End-Stage Liver Disease, vasopressor use). Areas under the receiver operating characteristic curve for early and late multivariable models were 0.778 and 0.907, respectively. The area under the receiver operating characteristic curve of the King's College criteria (early, 0.552 alone, 0.711 with FABP1; late, 0.604 alone, 0.797 with FABP1) and the Acute Liver Failure Study Group prognostic index (early, 0.686 alone, 0.766 with FABP1; late, 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (P < 0.002 for all). In patients with APAP-ALF, FABP1 may have good potential to discriminate survivors from nonsurvivors and may improve models currently used in clinical practice; validation of FABP1 as a clinical prediction tool in APAP-ALF warrants further investigation. (Hepatology 2017;65:938-949). © 2016 by the American Association for the Study of Liver Diseases.

  14. Necrostatin-1 protects against reactive oxygen species (ROS-induced hepatotoxicity in acetaminophen-induced acute liver failure

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    Kenji Takemoto

    2014-01-01

    Full Text Available Excessive acetaminophen (APAP use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK-dependent necrosis (or necroptosis, which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.

  15. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure

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    Takemoto, Kenji; Hatano, Etsuro; Iwaisako, Keiko; Takeiri, Masatoshi; Noma, Naruto; Ohmae, Saori; Toriguchi, Kan; Tanabe, Kazutaka; Tanaka, Hirokazu; Seo, Satoru; Taura, Kojiro; Machida, Keigo; Takeda, Norihiko; Saji, Shigehira; Uemoto, Shinji; Asagiri, Masataka

    2014-01-01

    Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure. PMID:25349782

  16. Reversal of bioenergetics dysfunction by diphenyl diselenide is critical to protection against the acetaminophen-induced acute liver failure.

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    Carvalho, Nélson R; Tassi, Cintia C; Dobraschinski, Fernando; Amaral, Guilherme P; Zemolin, Ana P; Golombieski, Ronaldo M; Dalla Corte, Cristiane L; Franco, Jeferson L; Mauriz, José L; González-Gallego, Javier; Soares, Félix A

    2017-07-01

    Physiopathological conditions such as acute liver failure (ALF) induced by acetaminophen (APAP) can often impair the mitochondrial bioenergetics. Diphenyl diselenide [(PhSe)2] has been shown protects against APAP-induced ALF. The present study aimed to clarify the signaling mechanism involved in the protection of bioenergetics dysfunction associated with ALF-induced by APAP overdose. Mice received APAP (600mg/kg) or (PhSe)2 (15.6mg/kg) alone, or APAP+(PhSe)2, all the solutions were administered by the intraperitoneal (i.p.). Samples of liver, blood and liver mitochondria were collected at 2 and 4h after APAP administration. APAP-induced ALF was able to induce ALF by means of alteration on liver injury biomarkers, increased Nitrite and Nitrate levels and the impairment of oxidative phosphorylation capacity (OXPHOS). In parallel, APAP overdose promoted activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heat shock protein 70 (HSP70) expression. (PhSe)2 was able to abolish the APAP-induced decline of OXPHOS and changes on the Nrf2-ARE pathway. In addition, (PhSe)2 elevated the levels of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), helping to restore the levels of nuclear respiratory factor 1 (NRF1) associated with mitochondrial biogenesis. In summary, the treatment with (PhSe)2 maintained mitochondrial function, promoted genes related to mitochondrial dynamic and demonstrating to play critical role in the modulation of cellular protective responses during ALF. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Translational biomarkers of acetaminophen-induced acute liver injury.

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    Beger, Richard D; Bhattacharyya, Sudeepa; Yang, Xi; Gill, Pritmohinder S; Schnackenberg, Laura K; Sun, Jinchun; James, Laura P

    2015-09-01

    Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

  18. Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

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    Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

    2016-01-01

    Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients. PMID:27550092

  19. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  20. Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices.

    Science.gov (United States)

    Ash, Stephen R; Caldwell, Cary A; Singer, Greg G; Lowell, Jeff A; Howard, Todd K; Rustgi, Vinod K

    2002-01-01

    When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.

  1. Sestrin2 protects against acetaminophen-induced liver injury.

    Science.gov (United States)

    Kim, Seung Jung; Kim, Kyu Min; Yang, Ji Hye; Cho, Sam Seok; Kim, Ji Young; Park, Su Jung; Lee, Sang Kyu; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2017-05-01

    Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    Science.gov (United States)

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  3. Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

    Science.gov (United States)

    Zhang, Jingyao; Zhang, Simin; Bi, Jianbin; Gu, Jingxian; Deng, Yan; Liu, Chang

    2017-04-01

    Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS

  4. Acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    Mossanen, J C; Tacke, F

    2015-04-01

    The induction of acute hepatic damage by acetaminophen (N-acetyl-p-aminophenol [APAP]), also termed paracetamol, is one of the most commonly used experimental models of acute liver injury in mice. The specific values of this model are the highly reproducible, dose-dependent hepatotoxicity of APAP and its outstanding translational importance, because acetaminophen overdose is one of the most frequent reasons for acute liver failure (ALF) in humans. However, preparation of concentrated APAP working solutions, application routes, fasting period and variability due to sex, genetic background or barrier environment represent important considerations to be taken into account before implementing this model. This standard operating procedure (SOP) provides a detailed protocol for APAP preparation and application in mice, aimed at facilitating comparability between research groups as well as minimizing animal numbers and distress. The mouse model of acetaminophen poisoning therefore helps to unravel the pathogenesis of APAP-induced toxicity or subsequent immune responses in order to explore new therapeutic interventions for improving the prognosis of ALF in patients.

  5. Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

    Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

  6. Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice.

    Science.gov (United States)

    Maes, Michaël; Crespo Yanguas, Sara; Willebrords, Joost; Weemhoff, James L; da Silva, Tereza Cristina; Decrock, Elke; Lebofsky, Margitta; Pereira, Isabel Veloso Alves; Leybaert, Luc; Farhood, Anwar; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2017-08-15

    Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Free radical scavenging activity of Berberine in acetaminophen induced liver injury

    Directory of Open Access Journals (Sweden)

    Suhail Ahmed Almani

    2017-01-01

    Full Text Available Objective: Evaluation of free radical scavenging activity of Berberine (BBR in acetaminophen (AAP induced liver injury. Study design: Experimental study Place and Duration: Animal house, Isra University Hyderabad from October 2015 to March 2016. Methodology: A sample of 80 male Wistar rats was selected according to inclusion and exclusion criteria and was divided into a control and three experimental groups. Acetaminophen, N-acetyl cysteine (NAC and BBR were administered in standard doses. Blood samples were collected by cardiac puncture after 18 hours of post experiment period. Liver function test, anti oxidant enzymes and malondialdehyde (MDA were detected by ELISA assay kit (Fortress Diagnostics. The data was analyzed on Statistix 10.0 software (USA at 95% CI (P≤ 0.05. Results: The BBR showed anti oxidant and anti peroxidant activity against acetaminophen induced liver injury. BBR treated animals showed increased serum and tissue SOD, GPX, CAT, and GSSH with a reduction in tissue MDA (p=0.0001. Liver injury ameliorating effect of BBR was superior to N-acetyl cysteine. Conclusion: The present study suggests Berberine protects against acetaminophen-induced liver injury by its free radical scavenging activity.

  8. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

    Directory of Open Access Journals (Sweden)

    H. P. Kopylchuk

    2017-04-01

    Full Text Available Arginase activity and L-arginine content in both cytosolic and mitochondrial fractions of rat liver cells under the conditions of toxic injury on the background of protein deprivation was studied. The most significant reduction of arginase activity in liver cells and depletion of L-arginine pool was found in rats with toxic acetaminophen-induced liver injury maintained on the ration balanced by all nutrients as well as in protein deficiency rats. It was concluded that reduction of the arginase activity in the cytosolic fraction of rat liver cells, combined with simultaneous decrease of L-arginine content, may be considered as one of the mechanisms of ornithine cycle disturbance. The decline of activity of mitochondrial isoform of arginase II, for certain, is related with activation of NO-synthase system.

  9. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...... performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 microg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase...... in AFP above 4 microg/L occurred in 158 (79%) of 201 survivors compared with 11 of 33 nonsurvivors (33%; P AFP occurred a mean of 1.0 days (range, -2 to +6 days) after peak ALT in survivors compared with 4.1 days (range, +2 to +7 days) in nonsurvivors (P

  10. Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway.

    Science.gov (United States)

    Suciu, Maria; Gruia, Alexandra T; Nica, Dragos V; Azghadi, Seyed M R; Mic, Ani A; Mic, Felix A

    2015-12-05

    Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis--were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen-induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology.

  11. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    Science.gov (United States)

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  12. Targeted metabolomic study indicating glycyrrhizin’s protection against acetaminophen-induced liver damage through reversing fatty acid metabolism.

    Science.gov (United States)

    Yu, Jian; Jiang, Yang-Shen; Jiang, Yuan; Peng, Yan-Fang; Sun, Zhuang; Dai, Xiao-Nan; Cao, Qiu-Ting; Sun, Ying-Ming; Han, Jing-Chun; Gao, Ya-Jie

    2014-06-01

    The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin-treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism.

  13. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; Ramachandran, Anup [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Breckenridge, David G.; Liles, John T. [Department of Biology, Gilead Sciences, Inc., Foster City, CA (United States); Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-07-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is

  14. Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice.

    Science.gov (United States)

    Ming, Ya-Nan; Zhang, Jing-Yi; Wang, Xiao-Lin; Li, Chun-Min; Ma, Si-Cong; Wang, Zheng-Yang; Liu, Xiao-Lin; Li, Xiao-Bo; Mao, Yi-Min

    2017-08-14

    Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice. A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high-throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot. Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt). Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver.

  15. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

    Science.gov (United States)

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP

  16. Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Sreenivasan Sasidharan

    2012-11-01

    Full Text Available The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05. Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

  17. Protective Properties of Flavonoid Extract of Coagulated Tofu (Curdled Soy Milk Against Acetaminophen-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Ndatsu Yakubu

    2016-01-01

    Full Text Available The total flavonoid contents of the various coagulated tofu and the hepatoprotective potential of all tofu flavonoid extracts were investigated. Tofu was prepared from locally sourced coagulants (steep water, alum, lemon, and lemon peel ash extract. Total flavonoid contents of all coagulated tofu were investigated as established in vitro flavonoid assay. The hepatoprotective activities of tofu flavonoid extracts against acetaminophen-induced hepatic cell toxicity in rats was also investigated in this study. The activity was analyzed by assessing the levels of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP and lactate dehydrogenase (LDH. The concentrations of the serum sugar, total protein, albumin, and cholesterol as well as prothrombin time (PT of experimental rats with histopathological analysis were also conducted. The range of the total flavonoid contents of tofu was 4.3-6.4 mg/g. Tofu flavonoid extracts significantly reduced the activities of serum AST, ALT, ALP, and LDH; total cholesterol, and sugar levels, but total protein and albumin concentrations increased compared to acetaminophen-intoxicated rats. Also, the prothrombin time prolongation of serum in acetaminophen intoxicated rats was reduced. Histology of the liver tissue demonstrated that tofu flavonoid extracts inhibited the acetaminophen-induced hepatic cell necrosis, decreased inflammatory cell infiltration and accelerated hepatocellular regeneration. Therefore, all tofus exhibited high total flavonoid contents, and the tofu supplement in human diets is highly recommended as it can be used as a functional food to prevent liver injuries.

  18. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  19. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Antonio Gonzalez-Ponce, Herson; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  20. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

    Directory of Open Access Journals (Sweden)

    Hyunseong Kim

    Full Text Available The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2 from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg in mice. Acetaminophen (APAP is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/- mice were injected with PLA2 once a day for five days and sacrificed 24 h (h after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST and alanine aminotransferase (ALT. PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  1. Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Bhushan, Bharat; Poudel, Samikshya; Manley, Michael W; Roy, Nairita; Apte, Udayan

    2017-03-01

    Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice. Treatment with specific GSK3 inhibitor (L803-mts), starting from 4 hours after 600 mg/kg dose of APAP, resulted in early initiation of liver regeneration in a dose-dependent manner, without modifying the peak regenerative response. Acceleration of liver regeneration was not secondary to alteration of APAP-induced hepatotoxicity, which remained unchanged after GSK3 inhibition. Early cell cycle initiation in hepatocytes after GSK3 inhibition was because of rapid induction of cyclin D1 and phosphorylation of retinoblastoma protein. This was associated with increased activation of β-catenin signaling after GSK3 inhibition. Taken together, our study has revealed a novel role of GSK3 in liver regeneration after APAP overdose and identified GSK3 as a potential therapeutic target to improve liver regeneration after APAP-induced ALF. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  2. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

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    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect from APAP

  3. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver

    Science.gov (United States)

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J.; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C.; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J.

    2017-01-01

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization. PMID:28134251

  4. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

    Science.gov (United States)

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; Del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C; Hayes, Peter C; Plevris, John N; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J

    2017-01-30

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.

  5. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

    Directory of Open Access Journals (Sweden)

    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  6. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Science.gov (United States)

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-l-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800 mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20 mmol/L APAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF. PMID:27782042

  7. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Directory of Open Access Journals (Sweden)

    Herson Antonio González-Ponce

    2016-10-01

    Full Text Available Acetaminophen (APAP-induced acute liver failure (ALF is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC, the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally. Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF.

  8. Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wang, Kun-Peng; Bai, Yu; Wang, Jian; Zhang, Jin-Zhen

    2014-05-01

    Schisandra chinensis is a well-known traditional medicinal herb. Acetaminophen is a commonly used over-the-counter analgesic and overdose of acetaminophen was the most frequent cause of acute liver failure. However, no studies have demonstrated the role of Schisandra chinensis in acetaminophen-induced acute liver failure to the best of our knowledge. In this study, an acute liver injury model was established in mice using acetaminophen. The protective role of Schisandra chinensis was detected by histopathological analysis, and measurement of the serum transaminase levels and hepatic Cyp activity levels in the mouse model. Subsequently, hepatocytes were isolated from the livers of the mouse model. The cell cycle, apoptosis, mitochondrial membrane potential and reactive oxygen species were determined using flow cytometry. Cell proliferation and 26S proteasome activity were determined using spectrophotometry. Schisandra chinensis was found to resist acetaminophen-induced hepatotoxicity by protecting mitochondria and lysosomes and inhibiting the phosphor-c-Jun N-terminal kinase signaling pathway. These findings provide a novel application of Schisandra chinensis against acetaminophen-induced acute liver failure.

  9. Protective effects of red wine polyphenols and grape-seed proanthocyanidin extract on acetaminophen-induced liver injury

    Directory of Open Access Journals (Sweden)

    El-Sayed M. El-Sayed

    2014-11-01

    Full Text Available The present study was designed to examine the potential protective effects of red wine polyphenols (RWPs and grape seed proanthocyanidin extract (GSPE against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard reference hepatoprotective agent. A single dose of acetaminophen (800 mg/kg, injected intraperitoneally to male rats, caused a significant increase in serum ALT, AST, alkaline phosphatase (ALP, bilirubin, total cholesterol (TC, triglycerides(TG, tumor necrosis factor alpha (TNF-α, and liver contents of thiobarbituric acid reactive substances (TBARS measured as malondialdehyde (MDA and nitric oxide (NO with significant decrease in serum albumin, HDL cholesterol, reduced glutathione (GSH and hepatic activities of catalase (CAT, superoxide dismutase (SOD and caspase-3 in liver tissue as compared with the control group. On the other hand, administration of each of GSPE (100 mg/kg/day, p.o., RWPs (40 mg/kg/day, p.o. and silymarin (100 mg/kg/day, p.o. for 15 consecutive days significantly ameliorated the liver injury which confirmed by the histopathological examination. It was concluded that RWPs and GSPE showed protective effects against acute acetaminophen hepatotoxicity where RWPs were more effective than GSPE; most probably through their antioxidant, anti-inflammatory and anti-apoptotic effects.

  10. [Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency].

    Science.gov (United States)

    Voloshchuk, O N; Kopylchuk, G P

    2016-01-01

    Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

  11. ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury.

    Science.gov (United States)

    Liao, Chia-Chih; Day, Yuan-Ji; Lee, Hung-Chen; Liou, Jiin-Tarng; Chou, An-Hsun; Liu, Fu-Chao

    2017-01-01

    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. 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.

  12. Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury

    Science.gov (United States)

    Graubardt, Nadine; Vugman, Milena; Mouhadeb, Odelia; Caliari, Gabriele; Pasmanik-Chor, Metsada; Reuveni, Debby; Zigmond, Ehud; Brazowski, Eli; David, Eyal; Chappell-Maor, Lousie; Jung, Steffen; Varol, Chen

    2017-01-01

    Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance. PMID:28620383

  13. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

    Science.gov (United States)

    Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Bersani-Amado, Ciomar Aparecida

    2017-01-01

    High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID:28717379

  14. Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury

    Science.gov (United States)

    Lu, Yan; Zhang, Cheng; Chen, Yuan-Hua; Wang, Hua; Zhang, Zhi-Hui; Chen, Xi; Xu, De-Xiang

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury. PMID:28205631

  15. Visualization of acetaminophen-induced liver injury by time-of-flight secondary ion mass spectrometry.

    Science.gov (United States)

    Murayama, Yohei; Satoh, Shuya; Hashiguchi, Akinori; Yamazaki, Ken; Hashimoto, Hiroyuki; Sakamoto, Michiie

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid-Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications.

  16. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  17. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice

    NARCIS (Netherlands)

    Swelm, R.P.L. van; Laarakkers, J.M.M.; Kuur, E.C. van der; Morava, E.; Wevers, R.A.; Augustijn, K.D.; Touw, D.J.; Sandel, M.H.; Masereeuw, R.; Russel, F.G.M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  18. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  19. Antioxidant and Hepatoprotective Properties of Tofu (Curdle Soymilk against Acetaminophen-Induced Liver Damage in Rats

    Directory of Open Access Journals (Sweden)

    Ndatsu Yakubu

    2013-01-01

    Full Text Available The antioxidant and hepatoprotective properties of tofu using acetaminophen to induce liver damage in albino rats were evaluated. Tofus were prepared using calcium chloride, alum, and steep water as coagulants. The polyphenols of tofu were extracted and their antioxidant properties were determined. The weight gain and feed intake of the rats were measured. The analysis of serum alanine aminotransferase (ALT, alkaline phosphatase (ALP, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH activities and the concentrations of albumin, total protein, cholesterol, and bilirubin were analyzed. The result reveals that the antioxidant property of both soluble and bound polyphenolic extracts was significantly higher in all tofus, but the steep water coagulated tofu was recorded higher. Rats fed with various tofus and acetaminophen had their serum ALP, ALT, AST, and LDH activities; total cholesterol; and bilirubin levels significantly (P<0.05 reduced, and total protein and albumin concentrations increased when compared with basal diet and acetaminophen administered group. Therefore, all tofus curdled with various coagulants could be used to prevent liver damage caused by oxidative stress.

  20. Inhibitor of Apoptosis Signal-Regulating Kinase 1 Protects Against Acetaminophen-induced Liver Injury

    Science.gov (United States)

    Xie, Yuchao; Ramachandran, Anup; Breckenridge, David G.; Liles, John T.; Lebofsky, Margitta; Farhood, Anwar; Jaeschke, Hartmut

    2015-01-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affected the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. PMID:25818599

  1. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level.

    Science.gov (United States)

    Fakurazi, S; Hairuszah, I; Nanthini, U

    2008-08-01

    Initiation of acetaminophen (APAP) toxicities is believed to be promoted by oxidative stress during the event of overdosage. The aim of the present study was to evaluate the hepatoprotective action of Moringa oleifera Lam (MO), an Asian plant of high medicinal value, against a single high dose of APAP. Groups of five male Sprague-Dawley rats were pre-administered with MO (200 and 800 mg/kg) prior to a single dose of APAP (3g/kg body weight; p.o). Silymarin was used as an established hepatoprotective drug against APAP induced liver injury. The hepatoprotective activity of MO extract was observed following significant histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in groups pretreated with MO compared to those treated with APAP alone. Meanwhile, the level of glutathione (GSH) was found to be restored in MO-treated animals compared to the groups treated with APAP alone. These observations were comparable to the group pretreated with silymarin prior to APAP administration. Group that was treated with APAP alone exhibited high level of transaminases and ALP activities besides reduction in the GSH level. The histological hepatocellular deterioration was also evidenced. The results from the present study suggested that the leaves of MO can prevent hepatic injuries from APAP induced through preventing the decline of glutathione level.

  2. Hepatoprotective Effect of ψ-Glutathione in a Murine Model of Acetaminophen-Induced Liver Toxicity.

    Science.gov (United States)

    More, Swati S; Nugent, Jaime; Vartak, Ashish P; Nye, Steffan M; Vince, Robert

    2017-03-20

    Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios. While both agents appear to be equally efficacious when timely administered, ψ-GSH partly retains its efficacy even in the face of substantial delay in administration. Thus, implied is the ability of ψ-GSH to intercept secondary toxicology following APAP insult. Oral availability and complete lack of toxicity as evaluated by liver function tests and survival analysis underscored ψ-GSH as a safer and more efficacious alternative to NAC. Finally, the pharmacodynamic mimicry of GSH by ψ-GSH is illustrated through the isolation and chemical characterization of an entity that can arise only through direct encounter of ψ-GSH with N-acetyl-p-benzoquinoneimine, the primary toxic metabolite of APAP.

  3. NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency

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    G. P. Kopylchuk

    2015-02-01

    Full Text Available The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADН is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences­ of energy exchange in the toxic hepatitis, induced on the background of protein deficiency.

  4. Remarks on Sasidharan et al. “Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage”. Molecules 2012, 17, 13937-13947

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    Manu Sharma

    2013-03-01

    Full Text Available An article by Sasidharan et al. recently published in the journal Molecules [1] claimed to show the hepatoprotective effects of lantadene A against acetaminophen-induced liver damage in mice. While reading this paper, I came across certain points that need to be clarified and taken up in the interest of science and other scientists working in this area.

  5. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

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    Patricia Rivera

    2017-10-01

    Full Text Available Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE-peroxisome proliferators activated receptor alpha (PPARα system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP, a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM and time-course (2–6–24 h study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH, including the NAEs oleoyl ethanolamide (OEA and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg. The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver

  6. Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice.

    Science.gov (United States)

    Salama, Mohamed; Elgamal, Mohamed; Abdelaziz, Azza; Ellithy, Moataz; Magdy, Dina; Ali, Lina; Fekry, Emad; Mohsen, Zinab; Mostafa, Mariam; Elgamal, Hoda; Sheashaa, Hussein; Sobh, Mohamed

    2015-07-01

    Acetaminophen (APAP, 4-hydroxyacetanilide) is the most common cause of acute liver failure in the United States. In addition to exhibiting hepatotoxicity, APAP exerts a nephrotoxic effect may be independent of the induced liver damage. Toll-like receptors (TLRs) have been suggested as a potential class of novel therapeutic targets. The aim of the present study was to investigate the potential of the TLR-4 blocker TAK-242 in the prevention of APAP-induced hepato-renal failure. Four groups of C57BL mice were studied: Vehicle-treated/control (VEH), APAP-treated (APAP), N-acetyl cysteine (NAC)-pretreated plus APAP (APAP + NAC) and TAK-242-pretreated plus APAP (APAP + TAK) groups. Mice were clinically assessed then perfused 4 h later. Liver and kidney tissues were collected and examined histologically using basic hematoxylin and eosin staining to detect signs of necrosis and inflammation. Plasma samples were collected to measure the levels of alanine transaminase, aspartate transaminase and serum creatinine. In addition, liver and kidney tissues were assayed to determine the levels of reduced glutathione. The results of the present study indicate the potential role of TLR-4 in APAP-induced organ toxicity. In the APAP + TAK and APAP + NAC groups, histopathological examination indicated that pretreatment with TAK-242 or NAC afforded protection against APAP-induced injury. However, this protective effect was more clinically evident in the APAP + TAK group compared with the APAP + NAC group. The various biochemical parameters (serum enzymes and reduced glutathione) revealed no significant protection in either of the pretreated groups. Therefore, the present study indicated that the TLR-4 blocker had protective effects against acute APAP toxicity in liver and kidney tissues. These effects were identified clinically, histologically and biochemically. Furthermore, the TLR-4 blocker TAK-242 exhibited antioxidant properties in addition to anti-inflammatory effects.

  7. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways

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    Fu-Chao Liu

    2016-01-01

    Full Text Available Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP- induced liver injury in a mice model. Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT and aspartate aminotransferase (AST levels, hepatic myeloperoxidase (MPO, malondialdehyde (MDA, glutathione (GSH, and superoxide dismutase (SOD activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting. Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK and extracellular signal-regulated kinase (ERK caused by APAP. Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice.

  8. Hepatoprotective Potential of Prosopis farcta Beans Extracts against Acetaminophen-induced Hepatotoxicity in Wister Rats

    OpenAIRE

    Akram Asadollahi; Hadi Sarir; Arash Omidi; Mohammad Bagher Montazar Torbati

    2014-01-01

    Background: Hepatotoxicity by acetaminophen is the most frequent cause of acute liver failure in many countries. Prosopis farcta beans extract (PFE) has some antioxidant property and may alleviate hepatotoxicity. Therefore, the aim of this study was to evaluate effects of PFE against acetaminophen-induced hepatotoxicity. Methods: Thirty-six male Wistar albino rats weighing 220 ± 30 g were distributed into six groups. Two groups were pretreated with PFE (50 and 75 mg/kg) for 7 days before ...

  9. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning.

    Science.gov (United States)

    Williams, C David; McGill, Mitchell R; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

  10. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice.

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    Rachel P L van Swelm

    Full Text Available Drug-induced liver injury (DILI is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP. Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT values (p<0.0001. Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001, including superoxide dismutase 1 (SOD1, carbonic anhydrase 3 (CA3 and calmodulin (CaM, as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001 in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.

  11. Protective effect of pioglitazone, a PPARγ agonist against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Gupta, Gaurav; Krishna, Gopala; Chellappan, Dinesh Kumar; Gubbiyappa, Kumar Shiva; Candasamy, Mayuren; Dua, Kamal

    2014-08-01

    Acetaminophen has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Pioglitazone, PPARγ ligand, is clinically tested and used in treatment of diabetes. PPARγ is a key nuclear hormone receptor of lipid metabolisms and regulates several gene transcriptions associated with differentiation, growth arrest, and apoptosis. The aim of our study was to evaluate the hepatoprotective activity of pioglitazone on acetaminophen-induced hepatotoxicity and to understand the relationship between the PPARγ and acetaminophen-induced hepato injury. For the experiment, Sprague-Dawley rats (160-180 g) were used and divided into four groups. Groups I and II were normal and experimental controls, respectively. Groups III and IV received the pioglitazone 20 mg/kg for 10 days. Hepatotoxicity was induced in Groups II and III on the eighth day with acetaminophen (i.p. 350 mg/kg body weight). The hepatoprotective effect was evaluated by performing an assay of the total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and α-fetoprotein as well as glutathione peroxidase, lipid peroxidation, catalase, superoxide dismutase, and glutathione transferase and liver histopathology. The assay results were presented as mean and standard error of mean for each group. The study group was compared with the control group by one-way ANOVA test. A p value of hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen -induced liver pathological damage. Various biochemical estimations of different hepatic markers and antioxidant enzymes and histopathological studies of liver tissues glimpse a support to its significant hepatoprotective activity on acetaminophen -induced hepatotoxicity.

  12. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

    Science.gov (United States)

    Patterson, Andrew D; Shah, Yatrik M; Matsubara, Tsutomu; Krausz, Kristopher W; Gonzalez, Frank J

    2012-07-01

    Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.

  13. The transcriptional change of mitochondrial genome in mice models for acetaminophen-induced acute liver injury and failure%对乙酰氨基酚诱导的急性肝损伤和肝衰竭模型中线粒体基因组转录改变

    Institute of Scientific and Technical Information of China (English)

    明雅南; 李春敏; 张静怡; 刘晓琳; 茅益民

    2016-01-01

    Objective To explore the relationship between transcription level of mitochondrial DNA (mtDNA ) and disease progression in the mice models of acetaminophen (APAP)‐induced acute liver injury (AILI) and acute liver failure (ALF) ,and to find the relative new biomarkers for outcome .Methods Ninety mice were randomly divided into three groups ,including control group ,AILI group (300 mg/kg) and ALF group (750 mg/kg) .After fasting 16 h ,all mice were intraperitoneally injected with same volume of saline or different doses of APAP .At different time points of 0 ,1 ,3 ,6 and 12 h , 6 mice randomly selected from each group were sacrificed for blood and liver , respectively . Plasma alanine aminotransferase (ALT ) ,aspartate aminotransferase (AST ) and reactive oxygen (ROS ) levels were detected ,and liver total RNA was extracted for RT‐PCR to detect changes in transcription of mitochondrial genome .Results Compared with the control group ,ALT and AST levels in AILI and ALF group were significantly increased .In AILI group ,ALT peaked at 6‐12 h (5000‐10000 IU/L) ,and ALT exceeded 10000 IU/L at 12 h in ALF group ,which showed significantly difference (P<0 .05) .Microbubbles steatosis in three zones was observed in both AILI and ALF groups ,and massive hepatic necrosis (MHN) were found merely in ALF group .In 1 h after APAP injection ,ROS in ALF group was about 2 .5 times as much as that in AILI group ,which significantly increased at all time points in both group .Contrasting with control and ALIF groups ,COX1 transcriptional level in AILI group increased significantly at 6 h .In AILI and ALF group ,CYTB ,COX2 and ATP8 reduced significantly at 3 h (P<0 .05) ,COX1 ,ND1 ,ND5 and ATP8 significantly decreased at 6 h (P<0 .05) ,and transcription level of other subunits of NADH significantly decreased at 12 h (P<0 .05) comparing with those in control group .Furthermore ,ATP6 at 6h in ALF group was obviously lower than that in AILI and control group (P<0 .05) .At 12 h

  14. Immune mediated liver failure

    OpenAIRE

    Wang, Xiaojing; Ning, Qin

    2014-01-01

    Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capac...

  15. Iridoid Glycosides Fraction Isolated from Veronica ciliata Fisch. Protects against Acetaminophen-Induced Liver Injury in Mice

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    Shancai Tan

    2017-01-01

    Full Text Available Veronica ciliata Fisch. has traditionally been used in Tibetan medicine for the treatment of hepatitis, cholecystitis, rheumatism, and urticaria. We analyzed the chemical composition of the iridoid glycosides fraction (IGF isolated from V. ciliata and evaluated the antioxidant and hepatoprotective properties. The IGF was separated by high-speed countercurrent chromatography (HSCCC and the main compounds were identified by ultra-performance liquid chromatography coupled to a photodiode array. We determined the in vitro antioxidant ability of the IGF through radical scavenging assays and assessed the in vivo hepatoprotective potential in an acetaminophen- (APAP- induced acute liver injury murine model. The IGF was separated by HSCCC and three major iridoid glycosides (verproside, catalposide, and amphicoside were identified as potent antioxidants and hepatoprotective compounds. Treatment with the IGF significantly suppressed the APAP-induced elevation in serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha (TNF-α; improved serum total antioxidant capacity; decreased malondialdehyde formation; elevated superoxide dismutase and glutathione activity; and decreased expression of proinflammatory factors (TNF-α, nuclear factor kappa B in the liver. Finally, we examined the histopathology of resected livers for evidence of hepatoprotection. The protection conferred by the IGF may be related to the reinforcement of antioxidant defense systems.

  16. Iridoid Glycosides Fraction Isolated from Veronica ciliata Fisch. Protects against Acetaminophen-Induced Liver Injury in Mice

    Science.gov (United States)

    Tan, Shancai; Lu, Qiuxia; Shu, Yueyue; Sun, Yiran

    2017-01-01

    Veronica ciliata Fisch. has traditionally been used in Tibetan medicine for the treatment of hepatitis, cholecystitis, rheumatism, and urticaria. We analyzed the chemical composition of the iridoid glycosides fraction (IGF) isolated from V. ciliata and evaluated the antioxidant and hepatoprotective properties. The IGF was separated by high-speed countercurrent chromatography (HSCCC) and the main compounds were identified by ultra-performance liquid chromatography coupled to a photodiode array. We determined the in vitro antioxidant ability of the IGF through radical scavenging assays and assessed the in vivo hepatoprotective potential in an acetaminophen- (APAP-) induced acute liver injury murine model. The IGF was separated by HSCCC and three major iridoid glycosides (verproside, catalposide, and amphicoside) were identified as potent antioxidants and hepatoprotective compounds. Treatment with the IGF significantly suppressed the APAP-induced elevation in serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha (TNF-α); improved serum total antioxidant capacity; decreased malondialdehyde formation; elevated superoxide dismutase and glutathione activity; and decreased expression of proinflammatory factors (TNF-α, nuclear factor kappa B) in the liver. Finally, we examined the histopathology of resected livers for evidence of hepatoprotection. The protection conferred by the IGF may be related to the reinforcement of antioxidant defense systems. PMID:28293265

  17. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

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    Takeshi Yamamotoya

    2017-02-01

    Full Text Available Linear ubiquitin chain assembly complex (LUBAC, composed of SHARPIN (SHANK-associated RH domain-interacting protein, HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1, and HOIP (HOIL-1L interacting protein, forms linear ubiquitin on nuclear factor-κB (NF-κB essential modulator (NEMO and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4 or acetaminophen (APAP, both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

  18. Reduced SHARPIN and LUBAC Formation May Contribute to CCl₄- or Acetaminophen-Induced Liver Cirrhosis in Mice.

    Science.gov (United States)

    Yamamotoya, Takeshi; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Yamazaki, Hiroki; Kaneko, Sunao; Fujishiro, Midori; Kikuchi, Takako; Kushiyama, Akifumi; Tokunaga, Fuminori; Asano, Tomoichiro; Sakoda, Hideyuki

    2017-02-04

    Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl₄) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

  19. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

    Science.gov (United States)

    Yamamotoya, Takeshi; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Yamazaki, Hiroki; Kaneko, Sunao; Fujishiro, Midori; Kikuchi, Takako; Kushiyama, Akifumi; Tokunaga, Fuminori; Asano, Tomoichiro; Sakoda, Hideyuki

    2017-01-01

    Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity. PMID:28165393

  20. Toxicity monitoring with primary cultured hepatocytes underestimates the acetaminophen-induced inflammatory responses of the mouse liver.

    Science.gov (United States)

    Tachibana, Shinjiro; Shimomura, Akiko; Inadera, Hidekuni

    2011-01-01

    In vitro gene expression profiling with isolated hepatocytes has been used to assess the hepatotoxicity of certain chemicals because of animal welfare issues. However, whether an in vitro system can completely replace the in vivo system has yet to be elucidated in detail. Using a focused microarray established in our laboratory, we examined gene expression profiles in the mouse liver and primary cultured hepatocytes after treatment with different doses of acetaminophen, a widely used analgesic that frequently causes liver injury. The acute hepatotoxicity of acetaminophen was confirmed by showing the induction of an oxidative stress marker, heme oxygenase-1, elevated levels of serum transaminase, and histopathological findings. In vivo microarray and network analysis showed that acetaminophen treatment provoked alterations in relation to the inflammatory response, and that tumor necrosis factor-α plays a central role in related pathway alterations. By contrast, pathway analyses in in vitro isolated hepatocytes did not find such prominent changes in the inflammation-related networks compared with the in vivo situation. Thus, although in vitro gene expression profiles are useful for evaluating the direct toxicity of chemicals, indirect toxicities including inflammatory responses mediated by cell-cell interactions or secondary toxicity due to pathophysiological changes in the whole body may be overlooked. Our results indicate that the in vitro hepatotoxicity prediction system using isolated hepatocytes does not fully reflect the in vivo cellular response. An in vitro system may be appropriate, therefore, for high throughput screening to detect the direct hepatotoxicity of a test compound.

  1. Methanol extract of Dicranopteris linearis L. leaves impedes acetaminophen-induced liver intoxication partly by enhancing the endogenous antioxidant system.

    Science.gov (United States)

    Zakaria, Zainul Amiruddin; Kamisan, Farah Hidayah; Omar, Maizatul Hasyima; Mahmood, Nur Diyana; Othman, Fezah; Abdul Hamid, Siti Selina; Abdullah, Muhammad Nazrul Hakim

    2017-05-18

    The present study investigated the potential of methanolic extract of Dicranopteris linearis (MEDL) leaves to attenuate liver intoxication induced by acetaminophen (APAP) in rats. A group of mice (n = 5) treated orally with a single dose (5000 mg/kg) of MEDL was first subjected to the acute toxicity study using the OECD 420 model. In the hepatoprotective study, six groups of rats (n = 6) were used and each received as follows: Group 1 (normal control; pretreated with 10% DMSO (extract's vehicle) followed by treatment with 10% DMSO (hepatotoxin's vehicle) (10% DMSO +10% DMSO)), Group 2 (hepatotoxic control; 10% DMSO +3 g/kg APAP (hepatotoxin)), Group 3 (positive control; 200 mg/kg silymarin +3 g/kg APAP), Group 4 (50 mg/kg MEDL +3 g/kg APAP), Group 5 (250 mg/kg MEDL +3 g/kg APAP) or Group 6 (500 mg/kg MEDL +3 g/kg APAP). The test solutions pre-treatment were made orally once daily for 7 consecutive days, and 1 h after the last test solutions administration (on Day 7th), the rats were treated with vehicle or APAP. Blood were collected from those treated rats for biochemical analyses, which were then euthanized to collect their liver for endogenous antioxidant enzymes determination and histopathological examination. The extract was also subjected to in vitro anti-inflammatory investigation and, HPLC and GCMS analyses. Pre-treatment of rats (Group 2) with 10% DMSO failed to attenuate the toxic effect of APAP on the liver as seen under the microscopic examination. This observation was supported by the significant (p < 0.05) increased in the level of serum liver enzymes of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), and significant (p < 0.05) decreased in the activity of endogenous antioxidant enzymes of catalase (CAT) and superoxide dismutase (SOD) in comparison to Group 1. Pre-treatment with MEDL, at all doses, significantly (p < 0.05) reduced the level of ALT and AST while the levels of CAT and SOD was

  2. Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.

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    Xiaoyan Lu

    Full Text Available The extent of drug-induced liver injury (DILI can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI, the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

  3. Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

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    Isaac Mohar

    2014-01-01

    Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

  4. Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

    Science.gov (United States)

    Dadhania, Vivekkumar P.; Bhushan, Bharat

    2017-01-01

    Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection. PMID:28210203

  5. Acute liver failure

    DEFF Research Database (Denmark)

    Larsen, Fin Stolze; Bjerring, Peter Nissen

    2011-01-01

    Acute liver failure (ALF) results in a multitude of serious complications that often lead to multi-organ failure. This brief review focuses on the pathophysiological processes in ALF and how to manage these.......Acute liver failure (ALF) results in a multitude of serious complications that often lead to multi-organ failure. This brief review focuses on the pathophysiological processes in ALF and how to manage these....

  6. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    Energy Technology Data Exchange (ETDEWEB)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  7. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.

    Science.gov (United States)

    McGill, Mitchell R; Williams, C David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity.

  8. Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells

    Directory of Open Access Journals (Sweden)

    Yu Ri Kim

    2013-01-01

    Full Text Available High doses of acetaminophen (APAP; N-acetyl-p-aminophenol cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10–50 mg/kg. Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1α, MIP-1β, IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

  9. Acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Lee, William M; Wendon, Julia

    2015-01-01

    Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized phenotype and disease course. Complex critical care protocols are now applied and emergency liver...

  10. Hepato-protective effects of six schisandra lignans on acetaminophen-induced liver injury are partially associated with the inhibition of CYP-mediated bioactivation.

    Science.gov (United States)

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Tan, Huasen; Chen, Pan; Zeng, Hang; Huang, Min; Bi, Huichang

    2015-04-25

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra fructus is widely-used traditional Chinese medicine which possesses hepato-protective potential. Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), and Schisantherin A (SthA) are the major bioactive lignans. Most recently, we found SolB exerts significant hepato-protection against APAP-induced liver injury. In this study, the protective effects of the other five schisandra lignans against APAP-induced acute hepatotoxicity in mice were investigated and compared with that of SolB. The results of morphological and biochemical assessment clearly demonstrated significant protective effects of SinA, SinB, SinC, SolA, SolB, and SthA against APAP-induced liver injury. Among these schisandra lignans, SinC and SolB exerted the strongest hepato-protective effects against APAP-induced hepatotoxicity. Six lignans pretreatment before APAP dosing could prevent the depletions of total liver glutathione (GSH) and mitochondrial GSH caused by APAP. Additionally, the lignans treatment inhibited the enzymatic activities of three CYP450 isoforms (CYP2E1, CYP1A2, and CYP3A11) related to APAP bioactivation, and further decreased the formation of APAP toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) in mouse microsomal incubation system. This study demonstrated that SinA, SinB, SinC, SolA, SolB and SthA exhibited significant protective actions toward APAP-induced liver injury, which was partially associated with the inhibition of CYP-mediated APAP bioactivation.

  11. [Nutrition and liver failure].

    Science.gov (United States)

    Plauth, M

    2013-06-01

    In the critically ill liver patient, nutrition support is not very different from that given for other illnesses. In hyperacute liver failure, nutrition support is of less importance than in the other subtypes of acute liver failure that take a more protracted course. Nasoenteral tube feeding using a polymeric standard formula should be the first-line approach, while parenteral nutrition giving glucose, fat, amino acids, vitamins, and trace elements is initiated when enteral nutrition is insufficient or impracticable. In chronic liver disease, notably cirrhosis, there is frequently protein malnutrition indicating a poor prognosis and requiring immediate initiation of nutrition support. Enteral nutrition ensuring an adequate provision of energy and protein should be preferred. Particular care should be taken to avoid refeeding syndrome and to treat vitamin and trace element deficiency.

  12. Transcriptomic studies on liver toxicity of acetaminophen.

    Science.gov (United States)

    Toska, Endrit; Zagorsky, Robert; Figler, Bryan; Cheng, Feng

    2014-09-01

    Acetaminophen is widely used as a pain reliever and to reduce fever. At high doses, it can cause severe hepatotoxicity. Acetaminophen overdose has become the leading cause of acute liver failure in the US. The mechanisms for acetaminophen-induced liver injury are unclear. Transcriptomic studies can identify the changes in expression of thousands of genes when exposed to supratherapeutic doses of acetaminophen. These studies elucidated the mechanism of acetaminophen-induced hepatotoxicity and also provide insight into future development of diagnosis and treatment options for acetaminophen-induced acute liver failure. The following is a brief overview of some recent transcriptomic studies and gene-expression-based prediction models on liver toxicity induced by acetaminophen.

  13. Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases.

    Science.gov (United States)

    Wang, Jun-Xian; Zhang, Cheng; Fu, Lin; Zhang, Da-Gang; Wang, Bi-Wei; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Chen, Xi; Xu, De-Xiang

    2017-01-04

    The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP)2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-κB) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex.

    Science.gov (United States)

    Onaolapo, Olakunle J; Adekola, Moses A; Azeez, Taiwo O; Salami, Karimat; Onaolapo, Adejoke Y

    2017-01-01

    We compared the relative protective abilities of silymarin and l-methionine pre-treatment in acetaminophen overdose injuries of the liver, kidney and cerebral cortex by assessing behaviours, antioxidant status, tissue histological changes and biochemical parameters of hepatic/renal function. Rats were divided into six groups of ten each; animals in five of these groups were pre-treated with oral distilled water, silymarin (25mg/kg) or l-methionine (2.5, 5 and 10mg/kg body weight) for 14days; and then administered intraperitoneal (i.p.) acetaminophen at 800mg/kg/day for 3days. Rats in the sixth group (normal control) received distilled water orally for 14days and then i.p. for 3days. Neurobehavioural tests were conducted 7days after last i.p treatment, and animals sacrificed on the 8th day. Plasma was assayed for biochemical markers of liver/kidney function; while sections of the liver, kidney and cerebral cortex were either homogenised for assay of antioxidant status or processed for histology. Acetaminophen overdose resulted in locomotor retardation, excessive self-grooming, working-memory impairment, anxiety, derangement of liver/kidney biochemistry, antioxidant imbalance, and histological changes in the liver, kidney and cerebral cortex. Administration of silymarin or increasing doses of l-methionine counteracted the behavioural changes, reversed biochemical indices of liver/kidney injury, and improved antioxidant activity. Silymarin and l-methionine also conferred variable degrees of tissue protection, on histology. Either silymarin or l-methionine can protect vulnerable tissues from acetaminophen overdose injury; however, each offers variable protection to different tissues. This study highlights an obstacle to seeking the 'ideal' protective agent against acetaminophen overdose.

  15. Defensive nature of Sargassum polycystum (Brown alga)against acetaminophen-induced toxic hepatitis in rats: Role of drug metabolizing microsomal enzyme system, tumor necrosis factor-α and fate of liver cell structural integrity

    Institute of Scientific and Technical Information of China (English)

    H Balaji raghavendran; A Sathivel; T Devaki

    2006-01-01

    AIM: To assess the defensive nature of Sargassum polycystum (S. Polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-α)and fine structural features of the liver during toxic hepatitis in rats.METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet.Group Ⅱ rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group Ⅲ rats were pre-treated with S. Polycystum extract alone.Group Ⅳ rats were orally pre-treated with S. Polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight,intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b5.Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy.RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b5 when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-α when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. Polycystum. The rats pretreated with S. Polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats,whereas the rats treated with S. Polycystum showed considerable protection against acetaminophen-induced alterations in

  16. Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage.

    Science.gov (United States)

    Bachmann, Malte; Waibler, Zoe; Pleli, Thomas; Pfeilschifter, Josef; Mühl, Heiko

    2017-01-01

    Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.

  17. Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage

    Science.gov (United States)

    Bachmann, Malte; Waibler, Zoe; Pleli, Thomas; Pfeilschifter, Josef; Mühl, Heiko

    2017-01-01

    Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression. PMID:28824623

  18. HEPATOPROTECTIVE EFFECT OF AQUEOUS AND N-HEXANE EXTRACT OF NIGELLA SATIVA IN PARACETAMOL (ACETAMINOPHEN INDUCED LIVER DISEASES OF RATS: A HISTOPATHOLOGICAL EVALUATION

    Directory of Open Access Journals (Sweden)

    Farida Yesmin

    2013-07-01

    Full Text Available Acute over dose of paracetamol (acetaminophen causes serious hepatic necrosis. So, this study was conducted to observe the hepatoprotective activity of aqueous and n-hexane extract of Nigella sativa in paracetamol induced hepatotoxicity in rats in Dhaka, Bangladesh from 2008 to 2010. Single dose of paracetamol was administered on day one and rats were sacrificed on day three. Liver damage was evaluated by hepatic histology. Aqueous and n-hexane extract of Nigella sativa was administered orally into two other rat groups through intra-gastric tube for 28 days in which paracetamol was administered orally on day 28 and were sacrificed on day 30. Liver of all rats were excised and processed for light microscopy with a view to histopathological evaluation. The histological examination of the liver tissues in vehicle treated group and paracetamol-control group of rats showed normal hepatic architecture, centrilobular necrosis, polymorph (neutrophils infiltration and pyknosis of the hepatocytes respectively. The hepatic architecture of rats pre-treated with aqueous extract of Nigella sativa showed improvement of necrosis with very few pyknotic nuclei when compared to the paracetamol-control group. The hepatic architecture of rats pre-treated with aqueous extract as well as with the n-hexane extract of Nigella sativa did not show pyknotic nuclei and polymorph infiltration while apparently regenerating hepatocytes, visible under the microscope. Aqueous extract and n-hexane extract of Nigella sativa extended hepatoprotection by reducing oxidative stress in experimental liver damage in rats. Furthermore, the protection afforded by the n-hexane extract of Nigella sativa pre-treated group was superior to the aqueous extract of Nigella sativa pre-treated group.

  19. Hepatoprotective and antioxidant effects of Azolla microphylla based gold nanoparticles against acetaminophen induced toxicity in a fresh water common carp fish (Cyprinus carpio L.

    Directory of Open Access Journals (Sweden)

    Selvaraj Kunjiappan

    2015-04-01

    Conclusion: Azolla microphylla phytochemically synthesized GNaP protects liver against oxidative damage and tissue damaging enzyme activities and could be used as an effective protector against acetaminophen-induced hepatic damage in fresh water common carp fish.

  20. Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver.

    Science.gov (United States)

    Hu, Jiangting; Ramshesh, Venkat K; McGill, Mitchell R; Jaeschke, Hartmut; Lemasters, John J

    2016-03-01

    Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and c-jun N-terminal kinase (JNK) activation. Because the safe limit of APAP dosing is controversial, our aim was to evaluate the role of the mitochondrial permeability transition (MPT) and JNK in mitochondrial dysfunction after APAP dosing considered nontoxic by criteria of serum alanine aminotransferase (ALT) release and histological necrosis in vivo. C57BL/6 mice were given APAP with and without the MPT inhibitor, N-methyl-4-isoleucine cyclosporin (NIM811), or the JNK inhibitor, SP600125. Fat droplet formation, cell viability, and mitochondrial function in vivo were monitored by intravital multiphoton microscopy. Serum ALT, liver histology, total JNK, and activated phospho(p)JNK were also assessed. High APAP (300 mg/kg) caused ALT release, necrosis, irreversible mitochondrial dysfunction, and hepatocellular death. By contrast, lower APAP (150 mg/kg) caused reversible mitochondrial dysfunction and fat droplet formation in hepatocytes without ALT release or necrosis. Mitochondrial protein N-acetyl-p-benzoquinone imine adducts correlated with early JNK activation, but irreversible mitochondrial depolarization and necrosis at high dose were associated with sustained JNK activation and translocation to mitochondria. NIM811 prevented cell death and/or mitochondrial depolarization after both high and low dose APAP. After low dose, SP600125 decreased mitochondrial depolarization. In conclusion, low dose APAP produces reversible MPT-dependent mitochondrial dysfunction and steatosis in hepatocytes without causing ALT release or necrosis, whereas high dose leads to irreversible mitochondrial dysfunction and cell death associated with sustained JNK activation. Thus, nontoxic APAP has the potential to cause transient mitochondrial dysfunction that may synergize with other stresses to promote liver damage and steatosis.

  1. A novel upregulation of glutathione peroxidase 1 by knockout of liver-regenerating protein Reg3β aggravates acetaminophen-induced hepatic protein nitration.

    Science.gov (United States)

    Yun, Jun-Won; Lum, Krystal; Lei, Xin Gen

    2013-12-01

    Murine regenerating islet-derived 3β (Reg3β) represents a homologue of human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein and enhances mouse susceptibility to acetaminophen (APAP)-induced hepatotoxicity. Our objective was to determine if and how knockout of Reg3β (KO) affects APAP (300 mg/kg, ip)-mediated protein nitration in mouse liver. APAP injection produced greater levels of hepatic protein nitration in the KO than in the wild-type mice. Their elevated protein nitration was alleviated by a prior injection of recombinant mouse Reg3β protein and was associated with an accelerated depletion of the peroxynitrite (ONOO(-)) scavenger glutathione by an upregulated hepatic glutathione peroxidase-1 (GPX1) activity. The enhanced GPX1 production in the KO mice was mediated by an 85% rise (pnitration and a new biosynthesis control of GPX1 by a completely "unrelated" regenerating protein, Reg3β, via transcriptional activation of Scly in coping with hepatic protein nitration. Linking selenoproteins to tissue regeneration will have profound implications in understanding the mechanism of Se functions and physiological coordination of tissue regeneration with intracellular redox control. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

    Science.gov (United States)

    Bandeira, Ana Carla Balthar; da Silva, Talita Prato; de Araujo, Glaucy Rodrigues; Araujo, Carolina Morais; da Silva, Rafaella Cecília; Lima, Wanderson Geraldo; Bezerra, Frank Silva; Costa, Daniela Caldeira

    2017-02-01

    Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo.

  3. Hepatho-nephroprotective and antioxidant effect of stem bark of Allanblackia gabonensis aqueous extract against acetaminophen-induced liver and kidney disorders in rats

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    Theophile Dimo

    2012-08-01

    Full Text Available Objective: Allanblackia gabonensis (Guttiferae is a plant used in traditional medicine to treat some inflammatory diseases. As oxidative stress promotes the development of acetaminophen (APAP-induced hepatotoxicity, the aim of the present study was to evaluate the hepato-nephroprotective and antioxidant effect of aqueous extract of A.gabonensis on APAP-induced liver and kidney damage. Methods: A.gabonensis was given daily per os during 7 days, followed by APAP which was given 2 h after the 6th dose for preventive effect, whereas for curative testing A.gabonensis was administrated 30 min after APAP (2 g/kg. Preventive and curative effects were observed by following biochemical parameters analysis: transaminases, bilirubin, creatinine, nitric oxide, malondialdehyde (MDA, glutathione (GSH, superoxide dismutase (SOD, and catalase (CAT. Results: The aqueous extract of A.gabonensis at the dose of 100 and 200 mg/kg produced significant hepato-nephroprotective activity by reducing the serum effect of MDA while it significantly produced an increase in enzymatic antioxidant activities (SOD and CAT and non enzymatic antioxidant (GSH levels. A.gabonensis also showed a significant decrease in transaminase, bilirubin and creatinine in APAP intoxicicated rats at the doses of 100 and 200 mg/kg. Conclusion: From this study it can be concluded that aqueous extract of A.gabonensis may possess hepato-nephroprotective activities which can be partly attributed to its antioxidant properties. [J Exp Integr Med 2012; 2(4: 337-344

  4. Hepatoprotective Effect of Polyphenol-Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen-Induced Liver Injury in Mice

    Science.gov (United States)

    Huang, Lisen; Pang, Haiyue; Zhang, Na; Chen, Yupei

    2017-01-01

    Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1–6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-β-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP-induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components. PMID:28626497

  5. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

    Science.gov (United States)

    Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

    2015-01-01

    Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients

  6. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  7. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    OpenAIRE

    Daniela Rodrigues; Themis Reverbel Da Silveira; Ursula Matte

    2012-01-01

    CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) ...

  8. Protective Effect of Acacia nilotica (L. against Acetaminophen-Induced Hepatocellular Damage in Wistar Rats

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    Narayanan Kannan

    2013-01-01

    Full Text Available The potential biological functions of A. nilotica have long been described in traditional system of medicine. However, the protective effect of A. nilotica on acetaminophen-induced hepatotoxicity is still unknown. The present study attempted to investigate the protective effect of A. nilotica against acetaminophen-induced hepatic damage in Wistar rats. The biochemical liver functional tests Alanine transaminase (ALT, Aspartate transaminase (AST, Alkaline phosphatase (ALP, total bilirubin, total protein, oxidative stress test (Lipid peroxidation, antioxidant parameter glutathione (GSH, and histopathological changes were examined. Our results show that the pretreatment with A. nilotica (250 mg/kg·bw orally revealed attenuation of serum activities of ALT, AST, ALP, liver weight, and total bilirubin levels that were enhanced by administration of acetaminophen. Further, pretreatment with extract elevated the total protein and GSH level and decreased the level of LPO. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by acetaminophen. The present study undoubtedly provides a proof that hepatoprotective action of A. nilotica extract may rely on its effect on reducing the oxidative stress in acetaminophen-induced hepatic damage in rat model.

  9. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    Attalla Farag El-Kott, PhD; Mashael Mohammed Bin-Meferij, PhD

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  10. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    Directory of Open Access Journals (Sweden)

    Maria Goretti R. Queiroz

    2008-10-01

    Full Text Available Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae leaf essential oil (EOCz was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o. acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT, serum glutamate oxaloacetate transaminase (GOT activities, that were significantly (p<0.01 elevated in the acetaminophen alone treated animals. Histopathological examinations of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in the acetaminophen treated group, while these were completely absent in the standard and EOCz treated groups. In conclusion, these data suggest that the Croton zehntneri essential oil can prevent hepatic injuries from acetaminophen-induced hepatotoxicity in mice.

  11. Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice.

    Science.gov (United States)

    Kawakami, Kayoko; Moritani, Chie; Uraji, Misugi; Fujita, Akiko; Kawakami, Koji; Hatanaka, Tadashi; Suzaki, Etsuko; Tsuboi, Seiji

    2017-03-01

    Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of γ-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against acetaminophen-induced hepatotoxicity in mice.

  12. Plasma Glutamine Concentrations in Liver Failure.

    Directory of Open Access Journals (Sweden)

    Gunnel Helling

    Full Text Available Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations.Four different groups of patients were studies; chronic liver failure (n = 40, acute on chronic liver failure (n = 20, acute fulminant liver failure (n = 20, and post-hepatectomy liver failure (n = 20. Child-Pugh and Model for End-stage Liver Disease (MELD scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion.All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100, severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong.Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure.

  13. Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling.

    Science.gov (United States)

    Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Hida, Shigeaki; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Nakamoto, Nobuhiro; Saito, Hidetsugu; Hibi, Toshifumi; Miura, Soichiro; Hokari, Ryota; Kanai, Takanori

    2017-05-26

    Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA. C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9(-/-)) mice and their Tlr9(+/+) littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses. The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs. HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism

  14. Preventive and curative effects of Acalypha indica on acetaminophen-induced hepatotoxicity

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    M Mathew

    2011-01-01

    Full Text Available Effect of ethanol extract of the leaves of Acalypha indica (Euphorbiaceae was investigated against acetaminophen-induced hepatic damage. Acetaminophen (paracetamol at the rate of 1 g/kg produced liver damage in rats as manifested by the significant (P<0.001 rise in serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, compared to respective control values. Treatment of rats with acetaminophen led to a marked increase in lipid peroxidation as measured by malondialdehyde (MDA. This was associated with a significant reduction in superoxide dismutase (SOD and glutathione (GSH contents. Pretreatment of animals with the plant extract (100 mg/kg orally once daily for 5 days prevented (P<0.01 the acetaminophen-induced rise in serum transaminases (AST and ALT and ALP. Post treatment with five successive doses of the extract (100 mg/kg restricted the hepatic damage induced by the above said Paracetamol (P<0.001. Histological changes around the hepatic central vein were recovered by administration of the drug. Thus, it is evident that these biochemical and histological alterations resulting from acetaminophen administration were inhibited by pre and post treatment with A. indica leaf extract. One notable study of the study was the spontaneous recovery of liver damage within a week after stopping paracetamol. These results indicate that the crude ethanol extract of A. indica exhibits hepatoprotective action through antioxidant effect and validates the traditional use of the plant in hepatic dysfunction.

  15. Micro-RNA-122 levels in acute liver failure and chronic hepatitis C.

    Science.gov (United States)

    Dubin, Perry H; Yuan, Hejun; Devine, Robert K; Hynan, Linda S; Jain, Mamta K; Lee, William M

    2014-09-01

    MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV-HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed. © 2014 Wiley Periodicals, Inc.

  16. Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

    Science.gov (United States)

    Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus.

  17. Artificial and bioartificial support systems for liver failure

    DEFF Research Database (Denmark)

    Liu, Jianping; Kjaergard, Lise Lotte; Als-Nielsen, Bodil;

    2002-01-01

    Liver support systems may bridge patients to liver transplantation or recovery from liver failure. This review is to evaluate the beneficial and harmful effects of artificial and bioartificial support systems for acute and acute-on-chronic liver failure.......Liver support systems may bridge patients to liver transplantation or recovery from liver failure. This review is to evaluate the beneficial and harmful effects of artificial and bioartificial support systems for acute and acute-on-chronic liver failure....

  18. Propylthiouracil-induced acute liver failure: role of liver transplantation.

    Science.gov (United States)

    Carrion, Andres F; Czul, Frank; Arosemena, Leopoldo R; Selvaggi, Gennaro; Garcia, Monica T; Tekin, Akin; Tzakis, Andreas G; Martin, Paul; Ghanta, Ravi K

    2010-01-01

    Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.

  19. Propylthiouracil-Induced Acute Liver Failure: Role of Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Andres F. Carrion

    2010-01-01

    Full Text Available Propylthiouracil- (PTU- induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.

  20. Pharm GKB: Liver Failure, Acute [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available UTR Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 144 Overview Alternate Names: Synonym ALF - Acute... liver failure; Acute Hepatic Failure; Acute Liver Failure; Acute hepatic failure; Acute... liver failure; FHF - Fulminant hepatic failure; Failure, Acute Hepatic; Failure, Acute... Liver; Fulminant hepatic failure; Hepatic Failure, Acute PharmGKB Accession Id: PA446443 External Voc...abularies MeSH: Liver Failure, Acute (D017114) SnoMedCT: Acute hepatic failure (197270009) SnoMedCT: Fulmina

  1. Acute liver failure and self-medication.

    Science.gov (United States)

    de Oliveira, André Vitorio Câmara; Rocha, Frederico Theobaldo Ramos; Abreu, Sílvio Romero de Oliveira

    2014-01-01

    Not responsible self-medication refers to drug use in high doses without rational indication and often associated with alcohol abuse. It can lead to liver damage and drug interactions, and may cause liver failure. To warn about how the practice of self-medication can be responsible for acute liver failure. Were used the Medline via PubMed, Cochrane Library, SciELO and Lilacs, and additional information on institutional sites of interest crossing the headings acute liver failure [tiab] AND acetaminophen [tiab]; self-medication [tiab] AND acetaminophen [tiab]; acute liver failure [tiab] AND dietary supplements [tiab]; self-medication [tiab] AND liver failure [tiab] and self-medication [tiab] AND green tea [tiab]. In Lilacs and SciELO used the descriptor self medication in Portuguese and Spanish. From total surveyed were selected 27 articles and five sites specifically related to the purpose of this review. Legislation and supervision disabled and information inaccessible to people, favors the emergence of cases of liver failure drug in many countries. In the list of released drugs that deserve more attention and care, are some herbal medicines used for the purpose of weight loss, and acetaminophen. It is recommended that institutes of health intensify supervision and better orient their populations on drug seemingly harmless, limiting the sale of products or requiring a prescription for release them.

  2. When the heart kills the liver: acute liver failure in congestive heart failure

    Directory of Open Access Journals (Sweden)

    Saner FH

    2009-12-01

    Full Text Available Abstract Congestive heart failure as a cause of acute liver failure is rarely documented with only a few cases. Although the pathophysiology is poorly understood, there is rising evidence, that low cardiac output with consecutive reduction in hepatic blood flow is a main causing factor, rather than hypotension. In the setting of acute liver failure due to congestive heart failure, clinical signs of the latter can be absent, which requires an appropriate diagnostic approach. As a reference center for acute liver failure and liver transplantation we recorded from May 2003 to December 2007 202 admissions with the primary diagnoses acute liver failure. 13/202 was due to congestive heart failure, which was associated with a mortality rate of 54%. Leading cause of death was the underlying heart failure. Asparagine transaminase (AST, bilirubin, and international normalized ratio (INR did not differ significantly in surviving and deceased patients at admission. Despite both groups had signs of cardiogenic shock, the cardiac index (CI was significantly higher in the survival group on admission as compared with non-survivors (2.1 L/min/m2 vs. 1.6 L/min/m2, p = 0.04. Central venous - and pulmonary wedge pressure did not differ significantly. Remarkable improvement of liver function was recorded in the group, who recovered from cardiogenic shock. In conclusion, patients with acute liver failure require an appropriate diagnostic approach. Congestive heart failure should always be considered as a possible cause of acute liver failure.

  3. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  4. SIRS score reflects clinical features of non-acetaminophen-related acute liver failure with hepatic coma.

    Science.gov (United States)

    Miyake, Yasuhiro; Yasunaka, Tetsuya; Ikeda, Fusao; Takaki, Akinobu; Nouso, Kazuhiro; Yamamoto, Kazuhide

    2012-01-01

    In acetaminophen-induced acute liver failure (ALF), the hepatic coma grade worsens and mortality rates increase, as the number of systemic inflammatory response syndrome components fulfilled (SIRS score) increases. This study aimed to investigate the impact of SIRS score on clinical features of non-acetaminophen-related ALF. Ninety-nine patients with non-acetaminophen-related ALF with hepatic coma who did not undergo liver transplantation were investigated. Each patient was given a SIRS score of 0, 1, 2, 3 or 4 at the time of diagnosis. At the diagnosis of ALF with hepatic coma, with the increase of SIRS score, hepatic coma grade and prothrombin activity were deteriorated. After the diagnosis of ALF with hepatic coma, 25 patients (25%) developed acute respiratory distress syndrome (ARDS), 31 patients (31%) developed disseminated intravascular coagulation (DIC), and 21 patients (22%) developed acute renal failure (ARF). Thirty-eight patients (38%) developed MOF. With the increase of SIRS score, frequencies of the development of ARDS, DIC and MOF increased. ARF was more frequently developed in patients with a SIRS score of 2 or higher. Overall, 36 patients (36%) survived. Overall survival rate was 66% in 29 patients with a score of 0, 43% in 21 patients with a score of 1, 17% in 29 patients with a score of 2 and 15% in 20 patients with a score of 3 or 4. SIRS score will be useful for predicting not only the overall survival but also the development of complications such as ARDS, DIC and MOF in non-acetaminophen-related ALF with hepatic coma.

  5. Clinical heterogeneity in autoimmune acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Norberto C Chavez-Tapia; Julio Martinez-Salgado; Julio Granados; Misael Uribe; Felix I Tellez-Avila

    2007-01-01

    AIM:To describe the outcome and prognosis in a cohort of patients with acute liver failure due to autoimmune hepatitis without liver transplantation.METHODS:A retrospective trial was conducted in 11 patients with acute liver failure due to autoimmune hepatitis who attended the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Demographic,biochemical and severity indexes,and treatment and outcome were assessed.RESULTS: Among the 11 patients, with a median age of 31 years, 72% had inflammatory response syndrome, and six patients received corticosteroids.The mortality rate within four weeks was 56%, and the one-year survival was 27%. In the survivors, severity indexes were lower and 83% received corticosteroids.CONCLUSION:We observed a relatively high survival rate in patients with acute liver failure due to autoimmune hepatitis. This survival rate could be influenced by severity of the disease and/or use of corticosteroids.

  6. Celecoxib-induced cholestatic liver failure requiring orthotopic liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Ihab I El Hajj; Shahid M Malik; Hany R Alwakeel; Obaid S Shaikh; Eizaburo Sasatomi; Hossam M Kandil

    2009-01-01

    Selective cyclooxygenase-2 (COX-2) inhibitors are widely used due to their efficacy and good safety profile.However, recent case reports have described varying degrees of liver injuries associated with the use of COX-2 inhibitors. We report the case of a patient who developed acute cholestatic hepatitis progressing to hepatic failure requiring liver transplantation, following a 3-d course of celecoxib for treatment of generalized muscle aches and pains. The clinical presentation, the laboratory data, as well as the liver histopathology were supportive of the putative diagnosis of drug induced liver injury.

  7. Therapeutic hypothermia for acute liver failure

    DEFF Research Database (Denmark)

    Stravitz, R.T.; Larsen, Finn Stolze

    2009-01-01

    of liver injury. Hypothermia has not been adequately studied for its safety and theoretically may increase the risk of infection, cardiac dysrhythmias, and bleeding, all complications independently associated with acute liver failure. Therefore, although an ample body of experimental and human data...... liver failure often can be temporarily controlled by manipulating body position, increasing the degree of sedation, and increasing blood osmolarity through pharmacologic means. However, these maneuvers often postpone, but do not eliminate, the risk of brainstem herniation unless orthotopic liver...... transplantation or spontaneous liver regeneration follows in short order. To buy time, the induction of therapeutic hypothermia (core temperature 32 degrees C-35 degrees C) has been shown to effectively bridge patients to transplant. Similar to the experience in patients with cerebral edema after other neurologic...

  8. Artificial and bioartificial support systems for liver failure

    DEFF Research Database (Denmark)

    Liu, J P; Gluud, L L; Als-Nielsen, B;

    2004-01-01

    Artificial and bioartificial liver support systems may 'bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery.......Artificial and bioartificial liver support systems may 'bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery....

  9. Acute-on-chronic Liver Failure.

    Science.gov (United States)

    Sarin, Shiv Kumar; Choudhury, Ashok

    2016-12-01

    Acute-on-chronic liver failure (ACLF) is a distinct entity that differs from acute liver failure and decompensated cirrhosis in timing, presence of treatable acute precipitant, and course of disease, with a potential for self-recovery. The core concept is acute deterioration of existing liver function in a patient of chronic liver disease with or without cirrhosis in response to an acute insult. The insult should be a hepatic one and presentation in the form of liver failure (jaundice, encephalopathy, coagulopathy, ascites) with or without extrahepatic organ failure in a defined time frame. ACLF is characterized by a state of deregulated inflammation. Initial cytokine burst presenting as SIRS, progression to CARS and associated immunoparalysis leads to sepsis and multi-organ failure. Early identification of the acute insult and mitigation of the same, use of nucleoside analogue in HBV-ACLF, steroid in severe alcoholic hepatitis, steroid in severe autoimmune hepatitis and/or bridging therapy lead to recovery, with a 90-day transplant-free survival rate of up to 50 %. First-week presentation is crucial concerning SIRS/sepsis, development, multiorgan failure and consideration of transplant. A protocol-based multi-disciplinary approach including critical care hepatology, early liver transplant before multi-organ involvement, or priority for organ allocation may improve the outcome. Presentation with extrahepatic organ involvement or inclusion of sepsis as an acute insult in definition restricts the therapy, i.e., liver transplant or bridging therapy, and needs serious consideration. Augmentation of regeneration, cell-based therapy, immunotherapy, and gut microbiota modulation are the emerging areas and need further research.

  10. Quercitrin from Toona sinensis (Juss. M.Roem. Attenuates Acetaminophen-Induced Acute Liver Toxicity in HepG2 Cells and Mice through Induction of Antioxidant Machinery and Inhibition of Inflammation

    Directory of Open Access Journals (Sweden)

    Van-Long Truong

    2016-07-01

    Full Text Available Quercitrin is found in many kinds of vegetables and fruits, and possesses various bioactive properties. The aim of the present study was to elucidate hepatoprotective mechanisms of quercitrin isolated from Toona sinensis (Juss. M.Roem. (syn. Cedrela sinensis Juss., using acetaminophen (APAP-treated HepG2 cell and animal models. In an in vitro study, quercitrin suppressed the production of reactive oxygen species and enhanced expression of nuclear factor E2-related factor 2 (Nrf2, activity of antioxidant response element (ARE-reporter gene, and protein levels of NADPH: quinone oxidoreductase 1 (NQO1, catalase (CAT, glutathione peroxidase (GPx, and superoxide dismutase 2 (SOD-2 in APAP-treated HepG2 cells. In an in vivo study, Balb/c mice were orally administered with 10 or 50 mg/kg of quercitrin for 7 days and followed by the injection with single dose of 300 mg/kg APAP. Quercitrin decreased APAP-caused elevation of alanine aminotransferase and aspartate aminotransferase levels, liver necrosis, the expression of pro-inflammatory factors including inducible nitric oxide synthase, cyclooxygenase 2 and inerleukin-1β, and phosphorylation of kinases including c-Jun N-terminal kinase and p38. Quercitrin restored protein levels of Nrf2, NQO1 and activities and expressions of CAT, GPx, SOD-2. The results suggested that quercitrin attenuates APAP-induced liver damage by the activation of defensive genes and the inhibition of pro-inflammatory genes via the suppressions of JNK and p38 signaling.

  11. Higher Thyroid-Stimulating Hormone, Triiodothyronine and Thyroxine Values Are Associated with Better Outcome in Acute Liver Failure.

    Directory of Open Access Journals (Sweden)

    Olympia Anastasiou

    Full Text Available Changes in thyroid hormone levels, mostly as non-thyroidal illness syndrome (NTIS, have been described in many diseases. However, the relationship between acute liver failure (ALF and thyroid hormone levels has not yet been clarified. The present study evaluates potential correlations of select thyroid functional parameters with ALF.84 consecutively recruited ALF patients were grouped according to the outcome of ALF (spontaneous recovery: SR; transplantation or death: NSR. TSH, free thyroxine (fT4, free triiodothyronine (fT3, T4, and T3 were determined.More than 50% of patients with ALF presented with abnormal thyroid parameters. These patients had greater risk for an adverse outcome than euthyroid patients. SR patients had significantly higher TSH, T4, and T3 concentrations than NSR patients. Albumin concentrations were significantly higher in SR than in NSR. In vitro T3 treatment was not able to rescue primary human hepatocytes from acetaminophen induced changes in mRNA expression.In patients with ALF, TSH and total thyroid hormone levels differed significantly between SR patients and NSR patients. This might be related to diminished liver-derived transport proteins, such as albumin, in more severe forms of ALF. Thyroid parameters may serve as additional indicators of ALF severity.

  12. Acetaminophen induces apoptosis in rat cortical neurons.

    Directory of Open Access Journals (Sweden)

    Inmaculada Posadas

    Full Text Available BACKGROUND: Acetaminophen (AAP is widely prescribed for treatment of mild pain and fever in western countries. It is generally considered a safe drug and the most frequently reported adverse effect associated with acetaminophen is hepatotoxicity, which generally occurs after acute overdose. During AAP overdose, encephalopathy might develop and contribute to morbidity and mortality. Our hypothesis is that AAP causes direct neuronal toxicity contributing to the general AAP toxicity syndrome. METHODOLOGY/PRINCIPAL FINDINGS: We report that AAP causes direct toxicity on rat cortical neurons both in vitro and in vivo as measured by LDH release. We have found that AAP causes concentration-dependent neuronal death in vitro at concentrations (1 and 2 mM that are reached in human plasma during AAP overdose, and that are also reached in the cerebrospinal fluid of rats for 3 hours following i.p injection of AAP doses (250 and 500 mg/kg that are below those required to induce acute hepatic failure in rats. AAP also increases both neuronal cytochrome P450 isoform CYP2E1 enzymatic activity and protein levels as determined by Western blot, leading to neuronal death through mitochondrial-mediated mechanisms that involve cytochrome c release and caspase 3 activation. In addition, in vivo experiments show that i.p. AAP (250 and 500 mg/kg injection induces neuronal death in the rat cortex as measured by TUNEL, validating the in vitro data. CONCLUSIONS/SIGNIFICANCE: The data presented here establish, for the first time, a direct neurotoxic action by AAP both in vivo and in vitro in rats at doses below those required to produce hepatotoxicity and suggest that this neurotoxicity might be involved in the general toxic syndrome observed during patient APP overdose and, possibly, also when AAP doses in the upper dosing schedule are used, especially if other risk factors (moderate drinking, fasting, nutritional impairment are present.

  13. Acute Liver Failure Secondary to Niacin Toxicity

    Directory of Open Access Journals (Sweden)

    Marc A. Ellsworth

    2014-01-01

    Full Text Available A 17-year-old male was transferred to the pediatric intensive care unit for evaluation of acute liver failure. He was recently released from an alcohol treatment center with acute onset of chest pain. Cardiac workup was negative but he was found to have abnormal coagulation studies and elevated liver transaminases. Other evaluations included a normal toxicology screen and negative acetaminophen level. Autoimmune and infectious workups were normal providing no identifiable cause of his acute liver failure. He initially denied any ingestions or illicit drug use but on further query he admitted taking niacin in an attempt to obscure the results of an upcoming drug test. Niacin has been touted on the Internet as an aid to help pass urine drug tests though there is no evidence to support this practice. Niacin toxicity has been associated with serious multisystem organ failure and fulminant hepatic failure requiring liver transplantation. Pediatric providers should be aware of the risks associated with niacin toxicity and other experimental medical therapies that may be described on the Internet or other nonreputable sources.

  14. Piperine, an active ingredient of black pepper attenuates acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Evan Prince Sabina; Annie Deborah Harris Souriyan; Deborah Jackline; Mahaboob Khan Rasool

    2010-01-01

    Objective: To explore the hepatoprotective and antioxidant effects of piperine against acetaminophen-induced hepatotoxicity in mice. Methods: In mice, hepatotoxicity was induced by a single dose of acetaminophen (900 mg/kg b.w. i.p.). Piperine (25 mg/kg b.w. i.p.) and standard drug silymarin (25 mg/kg b.w. i.p.) were given to mice, 30 min after the single injection of acetaminophen. After 4 h, the mice were decapitated. Activities of liver marker enzymes [(aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate of control and experimental mice. Results: Acetaminophen induction (900 mg/kg b.w. i.p.) significantly increased the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Piperine and silymarin treatment to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status. Conclusions: The results clearly demonstrate that piperine shows promising hepatoprotective effect as comparable to standard drug silymarin.

  15. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury.

    Science.gov (United States)

    Grespan, Renata; Aguiar, Rafael Pazinatto; Giubilei, Frederico Nunes; Fuso, Rafael Rocco; Damião, Marcio José; Silva, Expedito Leite; Mikcha, Jane Graton; Hernandes, Luzmarina; Bersani Amado, Ciomar; Cuman, Roberto Kenji Nakamura

    2014-01-01

    Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO), which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in mice. Their livers were then used to determine myeloperoxidase (MPO) enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•)-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice.

  16. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury

    Directory of Open Access Journals (Sweden)

    Renata Grespan

    2014-01-01

    Full Text Available Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO, which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, and alkaline phosphatase (ALP in mice. Their livers were then used to determine myeloperoxidase (MPO enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice.

  17. Steroid use in acute liver failure

    DEFF Research Database (Denmark)

    Karkhanis, Jamuna; Verna, Elizabeth C; Chang, Matthew S;

    2014-01-01

    UNLABELLED: 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...

  18. Antioxidant and hepatoprotective potential of Pouteria campechiana on acetaminophen-induced hepatic toxicity in rats.

    Science.gov (United States)

    Aseervatham, G Smilin Bell; Sivasudha, T; Sasikumar, J M; Christabel, P Hephzibah; Jeyadevi, R; Ananth, D Arul

    2014-03-01

    Pouteria campechiana (Kunth) Baehni. is used as a remedy for coronary trouble, liver disorders, epilepsy, skin disease, and ulcer. Therefore, the present study aims to investigate the antioxidant and hepatoprotective effect of polyphenolic-rich P. campechiana fruit extract against acetaminophen-intoxicated rats. Total phenolic and flavonoid contents of egg fruit were estimated followed by the determination of antioxidant activities. Treatment with P. campechiana fruit extract effectively scavenged the free radicals in a concentration-dependent manner within the range of the given concentrations in all antioxidant models. The presence of polyphenolic compounds were confirmed by high-performance thin-layer chromatography (HPTLC). The animals were treated with acetaminophen (250 mg/kg body weight; p.o.) thrice at the interval of every 5 days after the administration of P. campechiana aqueous extract and silymarin (50 mg/kg). Acetaminophen treatment was found to trigger an oxidative stress in liver, leading to an increase of serum marker enzymes. However, treatment with P. campechiana fruit extract significantly reduced the elevated liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) and increased the antioxidant enzymes (viz., superoxide dismutase and catalase) and glutathione indicating the effect of the extract in restoring the normal functional ability of hepatocytes. These results strongly suggest that P. campechiana fruit extract has strong antioxidant and significant hepatoprotective effect against acetaminophen-induced hepatotoxicity.

  19. "ACUTE LIVER FAILURE" : THE HEART MAY BE THE MATTER

    NARCIS (Netherlands)

    de Leeuw, K.; van der Horst, I. C. C.; van der Berg, A. P.; Ligtenberg, J. J. M.; Tulleken, J. E.; Zijlstra, J. G.; Meertens, John H. J. M.

    2011-01-01

    Hypoxic hepatitis secondary to heart failure is a known and treatable cause of liver failure. The diagnosis may be difficult, especially when symptoms of heart failure are absent. We present two patients who were transferred to our hospital with the diagnosis of acute liver failure to be screened fo

  20. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars;

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... endothelial activation. Here, we tested whether CD133 MP might be shed in a CD39-dependent manner in a model of liver injury and could potentially serve as biomarkers of liver failure in the clinic. METHODS: Wild-type and Cd39-null mice were subjected to acetaminophen-induced liver injury. Mice were...

  1. Imatinib-induced fatal acute liver failure

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d.Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor Ⅴ. Five days after admission, grade Ⅱ encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.

  2. the Pathogenesis of acute on Chronic Hepatitis B liver Failure

    Institute of Scientific and Technical Information of China (English)

    2014-01-01

    Acute-on-chronic liver failure is a characteristic clinical liver syndrome, which should be differentiated from acute liver failure, acute decompensated liver cirrhosis and chronic liver failure. The pathogenesis of ACLF is not fully understood yet. Viral factors and immune injury have been reported to be the two major pathogenesis. This paper reviewed the researches on the pathogenesis of acute on chronic hepatitis B liver failure in recent years, to provide theoretical basis for prompt and accurate diagnosis and treatment of this syndrome. This would beneift for the prognosis and raise the survival rate of patients.

  3. Drug –induced liver injury:a review

    Directory of Open Access Journals (Sweden)

    Sreya Kosanam

    2015-03-01

    Full Text Available The incidence of drug induced liver injury (DILI is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized based on the pattern of liver enzyme alteration (hepatocellular, cholestatic or mixed pattern, the mechanism of hepatotoxicity (direct, immune mediated or idiosyncratic and histologic findings on liver biopsy (steatosis or sinusoidal obstruction syndrome. Treatment options for DILI include discontinuing the drug, conservative measurements and liver transplantation in the case of non-acetaminophen induced hepatotoxicity.

  4. Plasma osteopontin in acute liver failure

    DEFF Research Database (Denmark)

    Srungaram, Praveen; Rule, Jody A; Yuan, He Jun

    2015-01-01

    BACKGROUND: Osteopontin (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. METHODS: OPN 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....../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...

  5. Prophylactic and Therapeutic Potential of Acetyl-L-carnitine against Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Alotaibi, Salman A; Alanazi, Abdulrazaq; Bakheet, Saleh A; Alharbi, Naif O; Nagi, Mahmoud N

    2016-01-01

    Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.

  6. Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Nesreen E.M. Mohammed

    2016-11-01

    Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

  7. Preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Yamada, S; Murawaki, Y; Kawasaki, H

    1993-09-14

    The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

  8. Gastrointestinal and Liver Issues in Heart Failure.

    Science.gov (United States)

    Sundaram, Varun; Fang, James C

    2016-04-26

    Heart failure affects ≈23 million people worldwide and continues to have a high mortality despite advancements in modern pharmacotherapy and device therapy. HF is a complex clinical syndrome that can result in the impairment of endocrine, hematologic, musculoskeletal, renal, respiratory, peripheral vascular, hepatic, and gastrointestinal systems. Although gastrointestinal involvement and hepatic involvement are common in HF and are associated with increased morbidity and mortality, their bidirectional association with HF progression remains poorly fathomed. The current understanding of multiple mechanisms, including proinflammatory cytokine milieu, hormonal imbalance, and anabolic/catabolic imbalance, has been used to explain the relationship between the gut and HF and has been the basis for many novel therapeutic strategies. However, the failure of these novel therapies such as anti-tumor necrosis factor-α has resulted in further complexity. In this review, we describe the involvement of the gastrointestinal and liver systems within the HF syndrome, their pathophysiological mechanisms, and their clinical consequences.

  9. A therapy for liver failure found in the JNK yard.

    Science.gov (United States)

    Willenbring, Holger; Grompe, Markus

    2013-04-11

    In the liver, the hepatocyte mass is kept stable through a tight balance between hepatocyte death and proliferation that is frequently lost upon acute or chronic liver injury. Wuestefeld et al. (2013) now identify a potentially druggable target that enhances hepatocyte proliferation and promotes liver regeneration, thereby preventing liver failure.

  10. Extracorporeal perfusion for the treatment of acute liver failure

    NARCIS (Netherlands)

    H.B.A.C. Stockmann; C.A. Hiemstra; R.L. Marquet (Richard); J.N.M. IJzermans (Jan)

    2000-01-01

    textabstractOBJECTIVE AND SUMMARY BACKGROUND DATA: Because of the shortage of available donor organs, death rates from liver failure remain high. Therefore, several temporary liver-assisting therapies have been developed. This article reviews various approaches to

  11. Extracorporeal perfusion for the treatment of acute liver failure

    NARCIS (Netherlands)

    H.B.A.C. Stockmann; C.A. Hiemstra; R.L. Marquet (Richard); J.N.M. IJzermans (Jan)

    2000-01-01

    textabstractOBJECTIVE AND SUMMARY BACKGROUND DATA: Because of the shortage of available donor organs, death rates from liver failure remain high. Therefore, several temporary liver-assisting therapies have been developed. This article reviews various approaches to tempo

  12. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

    Science.gov (United States)

    Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

    2017-04-04

    Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. Protective effects of pterostilbene against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    El-Sayed, El-Sayed M; Mansour, Ahmed M; Nady, Mohamed E

    2015-01-01

    The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

  14. Acetaminophen-Induced Acute Pancreatitis. A Case Report

    Directory of Open Access Journals (Sweden)

    Hisato Igarashi

    2009-09-01

    Full Text Available Context Drug-induced acute pancreatitis is rare but should not be overlooked in a patient who presents with idiopathic acute pancreatitis. More than 100 drugs have been implicated in causing the disease: acetaminophen has been associated with acute pancreatitis in cases where there has been an overdose of drugs; however, the frequency is rare. Case report We report the case of a 35-year-old woman who presented with acute pancreatitis and severe metabolic acidosis after overdosing on a drug containing acetaminophen. She improved dramatically after intensive care; however, she showed recurrent episodes after re-overdosing on the same drug. With her self re-challenge test, she was diagnosed as having acetaminophen-induced pancreatitis and metabolic acidosis. A review of the relevant literature is also presented. Conclusions Drug-induced acute pancreatitis is often challenging for clinicians and a detailed mechanism is unknown. It is very important to rule out drug-induced pancreatitis when treating pancreatitis with an unknown etiology.

  15. [Severe acute liver failure: a case study].

    Science.gov (United States)

    Moreno Arroyo, M Carmen; Puig Llobet, Montserrat; Cuervo Lavado, Luis

    2012-01-01

    Fulminant hepatic failure (FHF), also known as fulminant hepatitis, is a rare and extremely serious condition with a high mortality rate. Its rapid evolution and complexity in managing the treatment, creates the need to provide some immediate care by a team that specialises in intensive care. This acute decompensation is usually associated with other disorders, such as coagulopathy and hepatic encephalopathy, being responsible for major complications that can lead to organ failure. In our region the most common origin is unknown, followed by acute infection with hepatitis B. The treatment of this syndrome is based on the general measures applicable to any critically ill patient: treat the cause and early detection of extrahepatic complications, urgent liver transplantation being one of the alternatives with a better prognosis. This article presents a case report describing the monitoring of an Irish woman of 20 years who was transferred from a hospital in Ibiza to a hospital in Barcelona, with a suspected diagnosis of FHF. Following the conceptual model of Virginia Henderson, the collaborative problems and nursing diagnoses are described, presenting a care plan according to NANDA (North American Nursing Association), NIC (Nursing Intervention Classification), NOC (Nursing Outcomes Classification). This case helps to establish an individualised care plan that provides guidance to nurse professionals in critical patient care by increasing the knowledge of FHF.

  16. Reversal of intestinal failure-associated liver disease (IFALD)

    DEFF Research Database (Denmark)

    Hvas, Christian; Kodjabashia, Kamelia; Nixon, Emma

    2016-01-01

    Patients with intestinal failure (IF) and home parenteral nutrition commonly develop abnormal liver function tests. The presentations of IF-associated liver disease (IFALD) range from mild cholestasis or steatosis to cirrhosis and decompensated liver disease. We describe the reversal of IFALD in ...

  17. Acute liver failure associated with Garcinia cambogia use.

    Science.gov (United States)

    Corey, Rebecca; Werner, K Tuesday; Singer, Andrew; Moss, Adyr; Smith, Maxwell; Noelting, Jessica; Rakela, Jorge

    2016-01-01

    Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.

  18. Acute renal failure in liver transplant patients: Indian study.

    Science.gov (United States)

    Naik, Pradeep; Premsagar, B; Mallikarjuna, M

    2015-01-01

    The acute renal failure is the frequent medical complication observed in liver transplant patients. The objective of this study was to determine the cause of acute renal failure in post liver transplant patients. A total of 70 patients who underwent (cadaveric 52, live 18) liver transplantation were categorized based on clinical presentation into two groups, namely hepatorenal failure (HRF, n = 29), and Hepatic failure (HF, n = 41). All the patients after the liver transplant had received tacrolimus, mycophenolate and steroids. We analyzed the modification of diet in renal disease, (MDRD) serum urea, creatinine and albumin before and after 5th and 30th day of liver transplant and data was categorized into survivors and non-survivors group. In HRF survivor group, serum creatinine, and urea levels were high and, albumin, MDRD were low in pre- transplant and reached to normal levels on 30th day of post transplant, and 79.3 % of patients in this group showed resumption of normal kidney function. On the contrary in HRF nonsurvivor group, we did not observed any significant difference and 20.7 % of patients showed irreversible changes after the liver transplant. In HF survivor group, 82.9 % of liver failure patients did not show any deviation in serum creatinine, urea, albumin and MDRD, whereas in HF non survivor group, 17.1 % of liver failure patients who had HCV positive before the transplant developed acute renal failure. The levels of creatinine, urea, albumin and MDRD were normal before the transplant and on day 30th, the levels of albumin and MDRD were significantly low whereas serum urea, creatinine levels were high. In conclusion, based on these observations, an diagnosis and treatment of Acute renal failure is important among the liver transplantation cases in the early postoperative period.

  19. Acute-on-chronic liver failure: terminology, mechanisms and management.

    Science.gov (United States)

    Sarin, Shiv K; Choudhury, Ashok

    2016-03-01

    Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of disease and potential for unaided recovery. The definition involves outlining the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune dysregulation with initial wide-spread immune activation, a state of systematic inflammatory response syndrome and subsequent sepsis due to immune paresis. The disease severity and outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic regeneration during ongoing liver failure, although challenging, is possible through the use of growth factors. Liver transplantation remains the definitive treatment with a good outcome. Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.

  20. Acute liver failure associated with occupational exposure to tetrachloroethylene.

    Science.gov (United States)

    Shen, Chuan; Zhao, Cai-Yan; Liu, Fang; Wang, Ya-Dong; Wang, Wei

    2011-01-01

    Tetrachloroethylene is a chlorinated solvent that is primarily used in dry cleaning and degreasing operations. Although the hepatotoxicity caused by tetrachloroethylene has been well documented in literature, it is rarely considered as a cause of acute liver failure. We report a case of a 39-yr-old man who was admitted to our hospital for acute liver failure due to tetrachloroethylene exposure. Histological examination of the liver revealed massive hepatic necrosis, prominently, in zone 3 of the hepatic lobules. The patient underwent supportive treatment along with 3 sessions of plasmapheresis, and consequently, he presented a favorable outcome. Repeat liver biopsy performed 6 months after the patient's discharge showed architectural distortion with postnecrotic cirrhosis. Physicians should be aware of the possibility of acute liver failure induced by tetrachloroethylene. Early plasmapheresis can be effective for individuals with sufficient capacity for hepatocyte regeneration.

  1. Experimental models of hepatotoxicity related to acute liver failure

    Science.gov (United States)

    Maes, Michaël; Vinken, Mathieu; Jaeschke, Hartmut

    2015-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. PMID:26631581

  2. Predisposing Factors in Acute-on-Chronic Liver Failure

    DEFF Research Database (Denmark)

    Trebicka, J.

    2016-01-01

    Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality in patients with chronic liver disease. The definition of ACLF has been addressed recently in many publications, and despite regional differences the number and severity of organ failures are decisive for the prese...... hypertension might predispose for the development of ACLF after proper injury and response. © 2016 by Thieme Medical Publishers, Inc....

  3. Etiology and Outcome of Acute Liver Failure: Experience from a Liver Transplantation Centre in Montreal

    Directory of Open Access Journals (Sweden)

    Geneviève Tessier

    2002-01-01

    Full Text Available BACKGROUND: Acute liver failure is a rare condition in which massive liver injury is associated with the rapid development of hepatic encephalopathy. Although viral hepatitis and drug-induced liver injury are the most common causes, no specific etiology is found in a substantial proportion of cases reported from Europe and the United States.

  4. In vivo antioxidant activity of bark extract of Bixa orellana L. against acetaminophen- induced oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Smilin Bell Aseervatham G; Shamna R; Sangeetha B; Sasikumar JM

    2012-01-01

    Objective: To evaluate the in vivo activity of bark extract of Bixa orellana L. (B. orellana) against acetaminophen induced oxidative stress. Methods: In the present study, antioxidant activity ofB. orellana was evaluated by using normal and acetaminophen induced oxidative stressed rats at the dose of 100 mg/kg and 200 mg/kg p.o. oraly daily for 20 days. The animal's body weight was checked before and after treatment. Different biochemical parameters such as serum glutamate pyruvate transaminases, serum glutamate oxalo transaminases, alkaline phosphatase, total bilirubin, cholesterol, protein, lactate dehydrogenase, superoxide dismutase, catalase, ascorbic acid, lipid peroxide was performed. Histopathological analysis of the control and the hepatotoxicity induced rats were performed. Results: It was observed that the B. orellana bark extract showed significant protective activity against acetaminophen induced damage at 200 mg/kg dose level, while the 100 mg/kg dose showed moderate activity. Conclusions: From the result obtained in the present study suggest that B. orellana bark extract elicit protective activity through antioxidant activity on acetaminophen induced hepatic damage in rats.

  5. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    OpenAIRE

    Maria Goretti R. Queiroz; José Henrique L. Cardoso; Tomé, Adriana R; Roberto C. P. Lima Jr.; Jamile M. Ferreira; Daniel F. Sousa; Felipe C. Lima; Campos, Adriana R.

    2008-01-01

    Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae) leaf essential oil (EOCz) was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o.) acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT), serum glutamate oxaloacetate transaminase (GOT) activities, that were significantly (p

  6. Acute liver failure: An up-to-date approach.

    Science.gov (United States)

    Cardoso, Filipe S; Marcelino, Paulo; Bagulho, Luís; Karvellas, Constantine J

    2017-06-01

    Acute liver failure is a rare but potentially devastating disease. Throughout the last few decades, acute liver failure outcomes have been improving in the context of the optimized overall management. This positive trend has been associated with the earlier recognition of this condition, the improvement of the intensive care unit management, and the developments in emergent liver transplantation. Accordingly, we aimed to review the current diagnostic and therapeutic approach to this syndrome, especially in the intensive care unit setting. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. SURVIVAL OF LIVER CELLS, IMMOBILIZED ON 3D-MATRIXES, IN LIVER FAILURE MODEL

    Directory of Open Access Journals (Sweden)

    M. Y. Shagidulin

    2011-01-01

    Full Text Available It was examined a new method for correction of hepatic failure by transplantation of liver support biounit (liver cells, immobilized on biocompatible and biodegradable 3D-matrixes ElastoPOB® into small intestine mesentery. It was determined that after modeling of acute hepatic failure on dogs by 65–70% liver resection and transplantation liver support biounit the restoration of disturbed biochemical indecies (such as total protein, lactate, cytolytic ensymes-ALT, AST, ALP, LDH, fibrinogen, protrombine index and others took place more rapidly on 9–14th day instead of 18th day in control. It was made a preposition about efficiency of the suggested method for correction both acute hepatic failure because even 90 days after transplantation of liver support biounit alive hepatocytes and neogenic plethoric vessels, growing through matrix were revealed. 

  8. Angiosarcoma of the liver as a cause of fulminant liver failure

    Science.gov (United States)

    Montell García, Marco; Romero Cabello, Raúl; Romero Feregrino, Raul; Atri Moises, Mercado; Trejo Estrada, Rafael; Alvaro, Padilla-Rodríguez; Moreno Manlio Gerardo, Gama; Feregrino Rodrigo, Romero

    2012-01-01

    Primary liver sarcomas make up 2% of all malignant neoplasms of the liver; of these, angiosarcoma is the most common type. Primary liver tumours rarely cause fulminant hepatic failure (FHF), which is most frequently caused by non-neoplasmic pathologies. In the case of neoplasms, the most frequent are lymphoma and metastatic carcinomas. We describe the case of a 76-year-old man who suffered from FHF as a result of a liver angiosarcoma and we present a review of the medical literature in which we found only two cases of liver angiosarcomas linked to FHF. PMID:22865805

  9. Acute Liver Failure Secondary to Metastatic Medullary Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Emmanuel C. Gorospe

    2011-01-01

    Full Text Available Acute liver failure (ALF is a rare presentation of liver metastases. Although cases of ALF from metastatic disease have been reported, etiologies have been largely confined to lymphoma, metastatic breast, lung, and gastric cancers. ALF from medullary thyroid cancer (MTC has never been reported. We present a 59-year-old male with newly diagnosed MTC, who was admitted with ALF. He presented with jaundice, hepatic encephalopathy, and synthetic dysfunction. His clinical course was marked by rapid decompensation within 6 days from initial presentation of jaundice to development of hepatic coma. Although liver metastases from medullary thyroid cancer have been reported, to our knowledge, this is the first described case of MTC resulting in acute liver failure.

  10. [Citrullinemia type I with recurrent liver failure in a child].

    Science.gov (United States)

    Bindi, Verónica; Eiroa, Hernán

    2017-02-01

    Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors of metabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant.

  11. Thrombocytopenia Is Associated With Multi-organ System Failure in Patients With Acute Liver Failure

    NARCIS (Netherlands)

    Stravitz, R. Todd; Ellerbe, Caitlyn; Durkalski, Valerie; Reuben, Adrian; Lisman, Ton; Lee, William M.

    2016-01-01

    BACKGROUND & AIMS: Acute liver failure (ALF) is a syndrome characterized by an intense systemic inflammatory response (SIRS) and multi-organ system failure (MOSF). Platelet-derived microparticles increase in proportion to the severity of the SIRS and MOSF, and are associated with poor outcome. We in

  12. Apolipoprotein and lipid abnormalities in chronic liver failure

    Directory of Open Access Journals (Sweden)

    Spósito A.C.

    1997-01-01

    Full Text Available Total serum lipids, as well as apolipoproteins A-I (apo A-I and B (apo B, were determined in 74 patients with chronic liver failure without cholestasis and in 82 normal subjects. The VLDL, LDL and HDL lipid fractions were reduced in the liver failure group by 36%, 24% and 46%, respectively (P<0.001. Apolipoproteins A-I and B were also reduced by 26% and 25%, respectively (P<0.001. However, the reduction of HDL cholesterol (HDLc was more pronounced than that of apo A-I and the HDLc:apo A-I ratio was significantly lower in the liver failure group. After separating these patients into groups with plasma albumin lower than 3.0, between 3.0 and 3.5, and higher than 3.5 g/dl, the HDLc:apo A-I ratio was proportional to plasma albumin, but the correlation was not statistically significant. When these patients were separated by the Child classification of liver function, there was a correlation between the HDLc:apo A-I ratio and liver function. The differences in the HDLc:apo A-I ratio between the Child groups B and C, and A and C were statistically significant (P<0.05. We conclude that there is a more pronounced reduction in HDL cholesterol than in apo A-I in liver failure patients. Therefore, the HDLc:apo A-I ratio is a marker of liver function, probably because there is a decreased lecithin-cholesterol acyltransferase production by the diseased liver

  13. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  14. Acetaminophen Induced Hepatotoxicity in Wistar Rats--A Proteomic Approach.

    Science.gov (United States)

    Ilavenil, Soundharrajan; Al-Dhabi, Naif Abdullah; Srigopalram, Srisesharam; Ock Kim, Young; Agastian, Paul; Baru, Rajasekhar; Choi, Ki Choon; Valan Arasu, Mariadhas

    2016-01-28

    Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP) effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups--control, nontoxic (150 mg/kg) and toxic dose (1500 mg/kg) of APAP--were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD's PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%), immunity (14%), neurological related (12%) and transporter proteins (2%), whereas in non-toxic dose-induced rats they were oxidative stress (9%), immunity (6%), neurological (14%) and transporter proteins (9%). It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  15. Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

    Directory of Open Access Journals (Sweden)

    Soundharrajan Ilavenil

    2016-01-01

    Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  16. Satkara (Citrus macroptera Fruit Protects against Acetaminophen-Induced Hepatorenal Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Sudip Paul

    2016-01-01

    Full Text Available Although Citrus macroptera (Rutaceae, an indigenous fruit in Bangladesh, has long been used in folk medicine, however, there is a lack of information concerning its protective effects against oxidative damage. The protective effects of an ethanol extract of Citrus macroptera (EECM against acetaminophen-induced hepatotoxicity and nephrotoxicity were investigated in rats. Rats (treatment groups were pretreated with EECM at doses of 250, 500, and 1000 mg/kg, respectively, orally for 30 days followed by acetaminophen administration. Silymarin (100 mg/kg was administered as a standard drug over a similar treatment period. Our findings indicated that oral administration of acetaminophen induced severe hepatic and renal injuries associated with oxidative stress, as observed by 2-fold higher lipid peroxidation (TBARS compared to control. Pretreatment with EECM prior to acetaminophen administration significantly improved all investigated biochemical parameters, that is, transaminase activities, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transferase activities and total bilirubin, total cholesterol, triglyceride and creatinine, urea, uric acid, sodium, potassium and chloride ions, and TBARS levels. These findings were confirmed by histopathological examinations. The improvement was prominent in the group that received 1000 mg/kg EECM. These findings suggested that C. macroptera fruit could protect against acetaminophen-induced hepatonephrotoxicity, which might be via the inhibition of lipid peroxidation.

  17. Intestinal endotoxemia as a pathogenetic mechanism in liver failure

    Institute of Scientific and Technical Information of China (English)

    De-Wu Han

    2002-01-01

    Liver injury induced by various pathogenic factors (such as hepatitis virus, ethanol, drugs and hepatotoxicants, etc.)through their respective special pathogenesis is referred to as "primary liver injury" (PLI). Liver injury resultedfrom endotoxin (lipopolysaccharide, LPS) and the activation of Kupffer cells by LPS while intestinal endotoxemia (IETM) occurred during the occurrence and development of hepatitis is named the "secondary liver injury" (SLI).The latter which has lost their own specificities of primary pathogenic factors is ascribed to IETM. The "secondary liver injury" is of important action and impact on development and prognosis of hepatitis. More severe IETM commonly results in excessive inflammatory responses, with serious hepatic necrosis,further severe hepatitis and even induces acute liver failure.The milder IETM successively precipitates a cascade,including repeated and persistent hepatocytic impairment accompanied by infiltration of inflammatory cells, hepatic fibrosis, cirrhosis and hepatocarcinoma. Generally, the milder IETM ends with chronic hepatic failure. If PLI caused by various pathogenic factors through their independent specific mechanismis regarded as "the first hit" on liver, then SLI mediated by different chemical mediators from KCs activated by IETM in the course of hepatitis is "the second hit" on liver. Thus, fusing and overlapping of the primary and scondary liver injuries determine and influeuce the complexity of the illness and outcome of the patient with hepatitis. For this reason, the viewpoint of "SLI" induced by the "second hit" on liver inflicted by IFTM suggests that medical professionals should attach great importance to both "PLI"and "SLI" caused by IETM. That is, try to adjust the function of KSs and eliminate endotoxemia of the patient.

  18. Short day photoperiod protects against acetaminophen-induced ...

    African Journals Online (AJOL)

    Prof. Ogunji

    long photoperiod while these parameters were significantly (P<0.05) reduced in rats subjected to short .... Values are mean ± SEM with n=6. *P<0.05, ... result to serious liver injury or death in humans. (Watkins ... the rate-limiting enzyme in melatonin synthesis. (Illnerova ... Day length affects immune cells numbers in deer.

  19. Arterial ammonia levels in the management of fulminant liver failure

    Directory of Open Access Journals (Sweden)

    Curry S

    2011-06-01

    Full Text Available Previous studies have suggested that an arterial ammonia level greater than 150 mmol/L is highly sensitive for predicting subsequent development of cerebral edema in patients with fulminant liver failure. We performed a prospective cohort study to confirm this relationship. We enrolled 22 consecutive patients who presented to our transplant hepatology service with grade 3-4 encephalopathy associated with fulminant liver failure. All patients underwent placement of an intraparenchymal ICP monitor, and every 12 hourly arterial ammonia levels. The prevalence of intracranial hypertension (IHTN in our population was 95% (21/22 patients, with 82 discrete episodes recorded. The sensitivity of arterial ammonia levels to predict the onset of IHTN was 62% (95% CI: 40.8 to 79.3 at a cut point of 150 mmol/L. Arterial ammonia levels preceding the first intracranial hypertension event were less than 150 mmol/L in 8 of 21 patients (39%. Fifty nine of 82 episodes of IHTN (73% occurred when arterial ammonia levels were less than 150 mmol/L. We conclude that the arterial ammonia level is not useful in making decisions regarding management related to cerebral edema in patients with fulminant liver failure. In fact, since almost all our study patients with grade III or IV encephalopathy secondary to fulminant liver failure went on to develop intracranial hypertension, our study supports the contention that all such patients might benefit from ICP monitoring regardless of arterial ammonia levels.

  20. Angiosarcoma of the liver as a cause of fulminant liver failure

    OpenAIRE

    Montell García, Marco; Romero Cabello, Raúl; Romero Feregrino, Raul; Atri Moises, Mercado; Trejo Estrada, Rafael; Alvaro, Padilla-Rodríguez; Moreno Manlio Gerardo, Gama; Feregrino Rodrigo, Romero

    2012-01-01

    Primary liver sarcomas make up 2% of all malignant neoplasms of the liver; of these, angiosarcoma is the most common type. Primary liver tumours rarely cause fulminant hepatic failure (FHF), which is most frequently caused by non-neoplasmic pathologies. In the case of neoplasms, the most frequent are lymphoma and metastatic carcinomas. We describe the case of a 76-year-old man who suffered from FHF as a result of a liver angiosarcoma and we present a review of the medical literature in which ...

  1. Hepatic encephalopathy in acute-on-chronic liver failure.

    Science.gov (United States)

    Lee, Guan-Huei

    2015-10-01

    The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

  2. Acute kidney injury in acute liver failure: a review.

    Science.gov (United States)

    Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

    2013-11-01

    Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

  3. Macrophages and dendritic cells in the development of liver injury leading to liver failure.

    Science.gov (United States)

    Ananiev, J; Penkova, M; Tchernev, G; Chokoeva, A A; Philipov, S; Tana, C; Gulubova, M; Wollina, U

    2014-01-01

    Liver failure (LF) continues to be a serious problem due to different underlying disorders. Not only hepatocytes but Kupffer cells (KCs) and dendritic cells (DCs) are of importance in this instance. We wanted to investigate the possible role of KCs and liver DCs in the development of liver injury in patients with liver failure. Liver specimens from 23 patients who died after liver failure were examined for the presence and distribution of CD68-positive KCs and CD83-positive DCs by immunohistochemistry. The distribution of the CD83-positive DC in the sinusoidal and the periportal spaces was not even. While 39.1% of patients had a high sinusoidal density of CD83-positive cells, 60.9% demonstrated a high density of CD83-positive cells in the periportal tract. The number of CD83-positive DCs in periportal tracts in patients with advanced liver fibrosis (n=5) were high, while those with mild liver fibrosis (n=18) had low numbers of mature dendritic cells (χ2=4.107; p=0.043). In addition, all patients with intensive fibrosis had low counts of CD68-positive KC’s in portal tracts vs patients with mild fibrosis of which 67% had high counts (χ2=6.97; p=0.008). In seven of the patients with moderate steatosis (87.5%) low numbers of CD68-positive KCs were found in sinusoids, in contrast to those with severe steatosis, where 12 patients (80%) had high KC counts (χ2=13.4; p less than 0.001). The distribution and number of CD68-positive KC and CD83-positive DC reflect the progression of liver fibrosis leading to liver failure.

  4. Intestinal endotoxemia as a pathogenetic mechanism in liver failure

    Institute of Scientific and Technical Information of China (English)

    De-WuHan

    2002-01-01

    Liver injury induced by various pathogenic factors(such as hepatitis virus,ethanol,drugs and hepatotoxicants,etc.)through their respective special pathogenesis is referred to as“primary liver injury”(LPS)and the activation of kupffer cells by LPS while intestinal endotoxemia(IETM)occurted during the occurrence and development of hepatitis is named the“secondary liver injury”(SLI).The latter which has lost their own specificities of primary pathogenic factors is ascribed to IETM.The“secondary liver injury”is of important action and impact on development and prognosis of hepatitis.More severe IETM commonly results in excessive inflammatory responses,with serious hepatic necrosis,further severe hepatitis and even induces acute liver failure.The milder IETM successively precipitates a cascade,including repeated and persistent hepatocytic impairment accompanied by infiltration of inflammatory cells,hepatic fibrosis,cirrhosis and hepatocarcinoma.Generally,the milder IETM ends with chronic hepatic failure.If PLI caused by various pathogenic factors through their independent specific mechanismis regarded as“the first hit”on liver,then SLI mediated by different chemical mediators from KC,activated by IETMin the course of hepatitis is “the second hit”on liver.Thus,fusing and overlapping of the primary and scorndary liver injunies determine and influeuce the complexity of the illness and outcome of the patient with hepatitis.For this reason,the viewpoint of “SLI”induced by the “second hit”on liver inflicted by IETM suggests that medical professionals should attach great importance to both“PLI”and“SLI”caused by IETM.That is,try to adjust the function of KS,and eliminate endotoxemia ofthe patient.

  5. Encephalopathy in Wilson disease: copper toxicity or liver failure?

    Science.gov (United States)

    Ferenci, Peter; Litwin, Tomasz; Seniow, Joanna; Czlonkowska, Anna

    2015-03-01

    Hepatic encephalopathy (HE) is a complex syndrome of neurological and psychiatric signs and symptoms that is caused by portosystemic venous shunting with or without liver disease irrespective of its etiology. The most common presentation of Wilson disease (WD) is liver disease and is frequently associated with a wide spectrum of neurological and psychiatric symptoms. The genetic defect in WD leads to copper accumulation in the liver and later in other organs including the brain. In a patient presenting with Wilsonian cirrhosis neuropsychiatric symptoms may be caused either by the metabolic consequences of liver failure or by copper toxicity. Thus, in clinical practice a precise diagnosis is a great challenge. Contrary to HE in neurological WD consciousness, is very rarely disturbed and pyramidal signs, myoclonus dominate. Asterixis and many other clinical symptoms may be present in both disease conditions and are quite similar. However details of neurological assessment as well as additional examinations could help in differential diagnosis.

  6. Cerebral blood flow autoregulation in experimental liver failure

    DEFF Research Database (Denmark)

    Dethloff, T.J.; Larsen, F.S.; Knudsen, Gitte Moos

    2008-01-01

    Patients with acute liver failure (ALF) display impairment of cerebral blood flow (CBF) autoregulation, which may contribute to the development of fatal intracranial hypertension, but the pathophysiological mechanism remains unclear. In this study, we examined whether loss of liver mass causes...... impairment of CBF autoregulation. Four rat models were chosen, each representing different aspects of ALF: galactosamine (GlN) intoxication represented liver necrosis, 90% hepatectomy (PHx90) represented reduction in liver mass, portacaval anastomosis (PCA) represented shunting of blood....../toxins into the systemic circulation thus mimicking intrahepatic shunting in ALF, PCA+NH(3) provided information about the additional effects of hyperammonemia Rats were intubated and sedated with pentobarbital. We measured CBF with laser Doppler, intracranial pressure (ICP) was measured in the fossa posterior...

  7. Activation and Regulation of Hemostasis in Acute Liver Failure and Acute Pancreatitis

    NARCIS (Netherlands)

    Lisman, Ton; Porte, Robert J.

    2010-01-01

    Acute liver failure and acute pancreatitis are accompanied by substantial changes in the hemostatic system. In acute liver failure, defective synthesis of coagulation factors and intravascular activation of coagulation results in thrombocytopenia and reduced levels of proteins involved in coagulatio

  8. Acute liver failure and acute kidney injury: Definitions, prognosis, and outcome

    NARCIS (Netherlands)

    Włodzimirow, K.A.

    2013-01-01

    The objective of this thesis was to investigate definitions, prognostic indicators and their association with adverse events, mainly mortality for acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute kidney injury (AKI).

  9. Activation and Regulation of Hemostasis in Acute Liver Failure and Acute Pancreatitis

    NARCIS (Netherlands)

    Lisman, Ton; Porte, Robert J.

    Acute liver failure and acute pancreatitis are accompanied by substantial changes in the hemostatic system. In acute liver failure, defective synthesis of coagulation factors and intravascular activation of coagulation results in thrombocytopenia and reduced levels of proteins involved in

  10. Long-term prognosis for transplant-free survivors of paracetamol-induced acute liver failure

    DEFF Research Database (Denmark)

    Jepsen, P; Schmidt, L E; Larsen, F S

    2010-01-01

    The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown.......The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown....

  11. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Kuvandik, Guven; Duru, Mehmet; Nacar, Ahmet; Yonden, Zafer; Helvaci, Rami; Koc, Ahmet; Kozlu, Tolunay; Kaya, Hasan; Sogüt, Sadik

    2008-07-01

    We investigated the effects of erdosteine on acetaminophen (APAP)-induced hepatotoxicity in rats. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), AST (aspartate aminotransferase), and ALT (alanine transaminase) activities, and malonyldialdehyde (MDA) and nitric oxide levels as oxidant/antioxidant biochemical parameters were investigated with light microscopic evaluation in adult female Wistar Albino rats. APAP administration produced a decrease in hepatic SOD, CAT, and GSH-Px activities, and coadministration of erdosteine (150 and 300 mg/kg) resulted in increases in the activities. MDA and NO levels increased in the APAP group, and erdosteine treatments prevented these increases. Significant elevations in serum AST and ALT levels were observed in the APAP group, and when erdosteine and APAP were coadministered, their serum levels were close to those in the control group. Light microscopic evaluation of livers showed that there were remarkable centrilobular (zone III) hepatic necrosis and mild to moderate sinusoidal congestion in the APAP group, whereas in the erdosteine group, cellular necrosis was minimal and the hepatocytes maintained a better morphology when compared to the APAP group. Erdosteine prevented APAP-induced liver injury and toxic side effects probably through the antioxidant and radical scavenging effects of erdosteine.

  12. PREDICTION AND PREVENTION OF LIVER FAILURE AFTER MAJOR LIVER PRIMARY AND METASTATIC TUMORS RESECTION

    Directory of Open Access Journals (Sweden)

    A. D. Kaprin

    2016-01-01

    Full Text Available Abstract Purpose of the study. Improvement of results of treatment in patients with primary and metastatic liver cancer by decreasing the risk of post-resection liver failure on the basis of the evaluation of the functional reserves of the liver.Materials and Methods. The study included two independent samples of patients operated about primary or metastatic lesions of the liver at the Department of abdominal Oncology, P. A. Hertsen MORI. The first group included 53 patients who carried out 13C-breath test metallimovie and dynamic scintigraphy of the liver in the preoperative stage in addition to the standard algorithm of examination. Patients of the 2nd group (n=35 had a standard clinical and laboratory examination, the patients were not performed the preoperative evaluation of the functional reserve of the liver, the incidences of total bilirubin, albumin and prothrombin time did not reveal a reduction of liver function. Post-resection liver failure have been established on the basis of the 50/50 criterion in the evaluation on day 5 after surgery.Results. Analysis of operating characteristics of the functional tests showed the absolute methacin breath test sensitivity (SE≥100%, high specificity (SP≥67% of scintigraphy of the liver and the negative predictive value of outcome (VP≥100% at complex use of two diagnostic methods. The incidence of PROPS in the study group was significantly 2 times higher in the control group –15,1% and 26.8%, respectively (p<0.001.Conclusion. The combination of preoperative dynamic scintigraphy of the liver with carrying out 13C-breath methacin test allows you to conduct a comprehensive evaluation of the liver functional reserve and can significantly improve preoperative evaluation and postoperative results of anatomic resection in patients with primary and metastatic liver lesions.

  13. Kidney Failure and Liver Allocation: Current Practices and Potential Improvements.

    Science.gov (United States)

    Saxena, Varun; Lai, Jennifer C

    2015-09-01

    In February 2002, the United Network for Organ Sharing implemented a system for prioritizing candidates for liver transplantation that was based on the risk of 90-day mortality as determined by the Model for End-Stage Liver Disease (MELD) score. As the MELD score is driven in part by serum creatinine as a marker of kidney function, the prevalence of kidney dysfunction and failure in patients with end-stage liver disease at the time of listing and at transplantation has steadily risen. In this review, we discuss current practices in liver transplantation in patients with kidney dysfunction focusing briefly on the decision to perform simultaneous liver-kidney transplantation. We then discuss pitfalls to the current practices of liver transplantation in patients with kidney dysfunction. We conclude by discussing potential improvements to current practices including the use of the MELD-Na score, alternatives to creatinine and creatinine-based equation for estimating kidney function, and the use of intraoperative kidney replacement therapy during liver transplantation.

  14. Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication.

    Science.gov (United States)

    Olson, Jody C

    2016-07-01

    Chronic liver disease is the fifth leading cause of death worldwide and represents a major burden for the health care community. Cirrhosis is a progressive disease resulting in end-stage liver failure, which in the absence of liver transplantation is fatal. Acute-on-chronic liver failure carries high short-term mortality but is potentially reversible. Viral hepatitis, alcohol, and nonalcoholic fatty liver disease remain the principal causes of liver disease. Though treatments exist for hepatitis B and C, they remain unavailable to many with these diseases. This article reviews the epidemiology of advanced liver disease and the concept of acute-on-chronic liver failure.

  15. Auxiliary partial liver transplantation for acute liver failure using "high risk" grafts: Case report

    OpenAIRE

    Duan, Wei-Dong; Wang, Xi-Tao; Wang, Hong-Guang; Ji, Wen-Bin; Li, Hao; Jia-hong DONG

    2016-01-01

    Acute liver failure (ALF) is a reversible disorder that is associated with an abrupt loss of hepatic mass, rapidly progressive encephalopathy and devastating complications. Despite its high mortality, an emergency liver transplantation nowadays forms an integral part in ALF management and has substantially improved the outcomes of ALF. Here, we report the case of a 32-year-old female patient who was admitted with grade IV hepatic encephalopathy (coma) following drug-induced ALF. We performed ...

  16. Role of Protective Effect of L-Carnitine against Acute Acetaminophen Induced Hepatic Toxicity in Adult Albino Rats

    Directory of Open Access Journals (Sweden)

    Zeinab M. Gebaly* and Gamal M. Aboul Hassan

    2012-10-01

    Full Text Available Background: Acetaminophen, a widely used analgesic and antipyretic is known to cause hepatic injury in humans and experimental animals when administered in high doses. It was reported that toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. L-carnitine is a cofactor in the transfer of long-chain fatty acid allowing to the beta-oxidation of fatty acid in the mitochondria. It is a known antioxidant with protective effects against lipid peroxidation. This study aimed to investigate the possible beneficial effect of L-carnitine as an antioxidant agent against acetaminophen induced hepatic toxicity in rats. Material and Methods: Four rat groups (N=7 in each group. Group I is the control, group II received 500 mg/kg/ body weight of L-carnitine for 7 days by oral route, group III received 640/kg/ bw of acetaminophen by oral route, group IV acute acetaminophen group pretreated with L-carnitine for 7 days by gastric tube gavage tube. The liver of all rats were removed for investigation using light and electro microscopic studies. Results: Acetaminophen caused massive centrilobular necrosis and massive degenerative changes. The electron-microscopic study showed few mitochondria, increased fat droplets and scanty smooth endoplasmic reticulum (SER, rough endoplasmic reticulum (RER.These changes were reduced by L-carnitine pretreatment. Conclusion: those results suggest that acetaminophen results damage in the liver as an acute effect and L-carnitine ameliorated the adverse effects of acetaminophen via its antioxidant role

  17. Acute Liver Failure and Hepatic Encephalopathy After Cleft Palate Repair.

    Science.gov (United States)

    Kocaaslan, Nihal Durmuş; Tuncer, Fatma Betul; Tutar, Engin; Celebiler, Ozhan

    2015-09-01

    Paracetamol is the most commonly used analgesic after cleft palate repair. It has rarely caused acute hepatic failure at therapeutic or supratherapeutic doses. Only one case of therapeutic paracetamol toxicity after cleft palate repair had been reported previously. Here, we present a similar patient who developed acute liver failure and hepatic encephalopathy after an uncomplicated cleft palate surgery. Lack of large prospective trials in young children due to ethical concerns increases the value of the case reports of acetaminophen toxicity at therapeutic doses. The dosing recommendations of paracetamol may need to be reconsidered after cleft palate surgery.

  18. Dengue fever presenting as acute liver failure- a case report

    Institute of Scientific and Technical Information of China (English)

    Rajat Jhamb; Bineeta Kashyap; Ranga GS; Kumar A

    2011-01-01

    Dengue fever(DF) and dengue haemorrhagic fever(DHF) are important mosquito-borne viral diseases of humans and recognized as important emerging infectious diseases in the tropics and subtropics. Compared to nine reporting countries in the 1950s, today the geographic distribution includes more than100 countries worldwide. Dengue viral infections are known to present a diverse clinical spectrum, ranging from asymptomatic illness to fatal dengue shock syndrome. Mild hepatic dysfunction in dengue haemorrhagic fever is usual. However, its presentation as acute liver failure(ALF)is unusual. We report a patient with dengue shock syndrome who presented with acute liver failure and hepatic encephalopathy in a recent outbreak of dengue fever in Delhi, India.

  19. Methods of Liver Stem Cell Therapy in Rodents as Models of Human Liver Regeneration in Hepatic Failure.

    Science.gov (United States)

    Hashemi Goradel, Nasser; Darabi, Masoud; Shamsasenjan, Karim; Ejtehadifar, Mostafa; Zahedi, Sarah

    2015-09-01

    Cell therapy is a promising intervention for treating liver diseases and liver failure. Different animal models of human liver cell therapy have been developed in recent years. Rats and mice are the most commonly used liver failure models. In fact, rodent models of hepatic failure have shown significant improvement in liver function after cell infusion. With the advent of stem-cell technologies, it is now possible to re-programme adult somatic cells such as skin or hair-follicle cells from individual patients to stem-like cells and differentiate them into liver cells. Such regenerative stem cells are highly promising in the personalization of cell therapy. The present review article will summarize current approaches to liver stem cell therapy with rodent models. In addition, we discuss common cell tracking techniques and how tracking data help to direct liver cell therapy research in animal models of hepatic failure.

  20. Acute Liver Failure Secondary to Hemophagocytic Lymphohistiocytosis during Pregnancy

    OpenAIRE

    Giard, Jeanne-Marie; Decker, Kerry A.; Lai, Jennifer C.; Gill, Ryan M.; Logan, Aaron C.; Fix, Oren K.

    2016-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune activation that mimics and occurs with other systemic diseases. A 35-year-old female presented with signs of viral illness at 13 weeks of pregnancy and progressed to acute liver failure (ALF). We discuss the diagnosis of HLH and Kikuchi-Fujimoto (KF) lymphadenitis in the context of pregnancy and ALF. HLH may respond to comorbid disease-specific therapy, and more toxic treatment can be avoided.

  1. Gastric emptying in rats with acetaminophen-induced hepatitis

    Directory of Open Access Journals (Sweden)

    Hessel G.

    1998-01-01

    Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

  2. Extracorporeal liver support therapy with Prometheus in patients with liver failure in the intensive care unit.

    Science.gov (United States)

    Oppert, Michael; Rademacher, Sibylle; Petrasch, Kathrin; Jörres, Achim

    2009-10-01

    Acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF) are associated with a high mortality. In these patients an accumulation of both water-soluble and water-insoluble, protein-bound, metabolic waste products occurs. Conventional extracorporeal blood purification techniques based on diffusion and/or convection such as hemodialysis or hemofiltration may only eliminate small molecular weight, water-soluble compounds. In recent years, fractionated plasma separation and adsorption (FPSA) with the Prometheus system has been introduced for extracorporeal liver support therapy. To date, however, only limited data is available regarding the effect of this treatment on mortality and outcome of patients with advanced liver disease. Here we report on our experience with 23 patients with severe liver failure who were treated with Prometheus in our medical intensive care unit. Fourteen patients had AoCLF, and nine patients experienced ALF. The median bilirubin level at the start of Prometheus therapy was 30.5 mg/dL and the median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 26. During 40 individual treatment sessions lasting 5-6 h, Prometheus therapy reduced serum bilirubin levels from 23.7 mg/dL to 15.0 mg/dL (median values) (P Prometheus therapy was well tolerated without relevant side-effects. In conclusion, extracorporeal liver support therapy with Prometheus is a novel and safe treatment option in patients with severe liver failure. In this series, patients with ALF showed a significantly better outcome with Prometheus therapy compared to AoCLF patients.

  3. A comprehensive method for predicting fatal liver failure of patients with liver cancer resection.

    Science.gov (United States)

    Li, Jiangfa; Lei, Biao; Nie, Xingju; Lin, Linku; Tahir, Syed Abdul; Shi, Wuxiang; Jin, Junfei; He, Songqing

    2015-05-01

    There are many methods to assess liver function, but none of them has been verified as fully effective. The purpose of this study is to establish a comprehensive method evaluating perioperative liver reserve function (LRF) in patients with primary liver cancer (PLC).In this study, 310 PLC patients who underwent liver resection were included. The cohort was divided into a training set (n = 235) and a validation set (n = 75). The factors affecting postoperative liver dysfunction (POLD) during preoperative, intraoperative, and postoperative periods were confirmed by logistic regression analysis. The equation for calculating the preoperative liver functional evaluation index (PLFEI) was established; the cutoff value of PLFEI determined through analysis by receiver-operating characteristic curve was used to predict postoperative liver function.The data showed that body mass index, international normalized ratio, indocyanine green (ICG) retention rate at 15 minutes (ICGR15), ICG elimination rate, standard remnant liver volume (SRLV), operative bleeding volume (OBV), blood transfusion volume, and operative time were statistically different (all P POLD. The relationship among PLFEI, ICGR15, OBV, and SRLV is expressed as an equation of "PLFEI = 0.181 × ICGR15 + 0.001 × OBV - 0.008 × SRLV." The cutoff value of PLFEI to predict POLD was -2.16 whose sensitivity and specificity were 90.3% and 73.5%, respectively. However, when predicting fatal liver failure (FLF), the cutoff value of PLFEI was switched to -1.97 whose sensitivity and specificity were 100% and 68.8%, respectively.PLFEI will be a more comprehensive, sensitive, and accurate index assessing perioperative LRF in liver cancer patients who receive liver resection. And keeping PLFEI <-1.97 is a safety margin for preventing FLF in PLC patients who underwent liver resection.

  4. Effect of IL-10 mRNA expression in acetaminophen-induced hepatotoxicity%白细胞介素-10mRNA表达在对乙酰氨基酚所致肝损害中的作用

    Institute of Scientific and Technical Information of China (English)

    田丰; 解莹; 张亚杰

    2012-01-01

    Objective To investigate the role of interleukin-10( IL-10 ) in acetaminophen-induced hepatotoxic-ity. Methods To establish the model of acetaminophen-induced hepatotoxicity in SD rats. The levels of serum ALT of AAP group and control group were measured by radioimmunoassay. Hepatic tissue samples were taken to evaluate pathological changes by HE staining and the IL-10 mRNA expression was detected by RT-PCR. Results Compared to control group, serum ALT( nKat/L )were progressively increased after acetaminophen administration( P < 0. 01 )in different time periods; Liver pathological damage were progressively exacerbated; The expression of IL-10 mRNA in liver tissue increased significantly( P <0. 01 ),and reached a peak at 12 h. Conclusion IL-10 has a strong inhibitory effect on pro-inflammatory cytokine expression, which may play a protective role in acetaminophen-induced hepatotoxicity.%目的 探讨白细胞介素-10(IL-10)在AAP肝损害中的作用.方法 应用对乙酰氨基酚(AAP)建立SD大鼠肝损害模型;AAP组和对照组分别测定血清ALT水平,HE染色观察肝脏病理变化,RT-PCR方法检测大鼠肝组织中IL-10 mRNA的表达.结果 AAP组和对照组相比,各时间点血清ALT水平均显著升高(P<0.01);肝脏病理损伤进行性加剧;肝组织IL-10 mRNA表达显著升高(P<0.01),于12 h达高峰.结论 IL-10可能具有抑制促炎因子表达作用,在AAP引起的肝损害中可能起到肝脏保护作用.

  5. Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose.

    Science.gov (United States)

    Shirota, Tomoki; Ikegami, Toshihiko; Sugiyama, Satoshi; Kubota, Kouji; Shimizu, Akira; Ohno, Yasunari; Mita, Atsuyoshi; Urata, Koichi; Nakazawa, Yuichi; Kobayashi, Akira; Iwaya, Mai; Miyagawa, Shinichi

    2015-04-01

    A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient's mother. Following transplantation, the patient's renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation.

  6. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography

    NARCIS (Netherlands)

    Stravitz, R. Todd; Lisman, Ton; Luketic, Velimir A.; Sterling, Richard K.; Puri, Puneet; Fuchs, Michael; Ibrahim, Ashraf; Lee, William M.; Sanyal, Arun J.

    2012-01-01

    Background & Aims: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. Methods: Fifty-one pa

  7. Extracorporeal support for patients with acute and acute on chronic liver failure.

    Science.gov (United States)

    Aron, Jonathan; Agarwal, Banwari; Davenport, Andrew

    2016-01-01

    The number of patients developing liver failure; acute on chronic liver failure and acute liver failure continues to increase, along with the demand for donor livers for transplantation. As such there is a clinical need to develop effective extracorporeal devices to support patients with acute liver failure or acute-on-chronic liver failure to allow time for hepatocyte regeneration, and so avoiding the need for liver transplantation, or to bridge the patient to liver transplantation, and also potentially to provide symptomatic relief for patients with cirrhosis not suitable for transplantation. Currently devices can be divided into those designed to remove toxins, including plasma exchange, high permeability dialyzers and adsorption columns or membranes, coupled with replacement of plasma proteins; albumin dialysis systems; and bioartificial devices which may provide some of the biological functions of the liver. In the future we expect combinations of these devices in clinical practice, due to the developments in bioartificial scaffolds.

  8. Liver myofibroblasts up-regulate monocyte CD163 expression via PGE2 during hepatitis B induced liver failure.

    Science.gov (United States)

    Zhang, Min; Ye, Yinong; Wang, Fenglan; Zhu, Jianyun; Zhao, Qiyi; Zheng, Yubao; Gu, Yurong; Xie, Chan; Huang, Zhanlian; Tai, Qiang; Chong, Yutian; Gao, Zhiliang

    2014-03-06

    Although patients with liver failure exhibit a generalized inflammatory-imbalance status, substantial evidence indicates that this immunosuppressive or anti-inflammatory state may be deleterious. Increased expression of CD163 (known to be involved in several anti-inflammatory functions of the immune system) in patients with liver failure is significantly correlated with a fatal outcome. However, little is known of the regulatory mechanisms that influence the expression of CD163. We assessed the expression of CD163 on monocytes from both circulating cells and the liver tissues of patients with hepatitis B induced liver failure using flow cytometry and isolated the myofibroblasts from diseased livers. The ability of human liver myofibroblasts to regulate CD163 expression on monocytes was studied in vitro. We showed that CD163⁺ monocytes were enriched primarily in diseased livers and that they were associated with liver myofibroblasts in the same area. Accordingly, liver myofibroblasts were significantly superior to normal skin fibroblasts in inducing the expression of CD163 on monocytes in vitro. Moreover, we found that liver myofibroblasts triggered the activation of monocytes by secreting PGE2. Inhibition of PGE2 production in liver myofibroblasts using NS-398 markedly reduced CD163 expression in vitro. These results suggest that liver myofibroblasts play a direct role in regulating the expression of CD163 on monocytes in human liver tissues and thereby may regulate monocyte function during hepatitis B induced liver failure.

  9. Diagnostic criteria for acute liver failure due to Wilson disease

    Institute of Scientific and Technical Information of China (English)

    Christoph Eisenbach; Olivia Sieg; Wolfgang Stremmel; Jens Encke; Uta Merle

    2007-01-01

    AIM: To describe the diagnostic criteria for acute liver failure due to Wilson disease (WD), which is an uncommon cause of acute liver failure (ALF).METHODS: We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies.RESULTS: Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate aminotransferase (AST) to alanine aminotransferase (ALT), failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities (53 ± 43 vs 1982 ± 938, P < 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively), low choline esterase activity (1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009), high urine copper concentrations (93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001) and low hemoglobin (7.0 ± 2.2 vs 12.6 ± 1.8, P < 0.0001) in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation.CONCLUSION: In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slit-lamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.

  10. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    Science.gov (United States)

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases.

  11. Acute liver failure: a critical appraisal of available animal models.

    Science.gov (United States)

    Bélanger, Mireille; Butterworth, Roger F

    2005-12-01

    The availability of adequate experimental models of acute liver failure (ALF) is of prime importance to provide a better understanding of this condition and allow the development and testing of new therapeutic approaches for patients with ALF. However, the numerous etiologies and complications of ALF contribute to the complexity of this condition and render the development of an ideal experimental model of ALF more difficult than expected. Instead, a number of different models that may be used for the study of specific aspects of ALF have been developed. The most common approaches used to induce ALFin experimental animals are surgical procedures, toxic liver injury,or a combination of both. Despite the high prevalence of viral hepatitis worldwide, very few satisfactory viral models of ALF are available. Established and newly developed models of ALF are reviewed.

  12. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF)

    DEFF Research Database (Denmark)

    Grønbæk, Henning; Rødgaard-Hansen, Sidsel; Aagaard, Niels Kristian

    2016-01-01

    BACKGROUND & AIMS: Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor...

  13. Acute liver failure due to non-exertional heatstroke after sauna.

    Science.gov (United States)

    Erarslan, Elife; Yüksel, Ilhami; Haznedaroglu, Serap

    2012-01-01

    Acute liver failure is defined as rapid loss of liver function that patients without previously recognized liver disease sustain a liver damage. Acute liver failure due to non-exertional heatstroke has rarely been reported. We reported here an unusual case of heat stroke induced acute liver failure (ALF) after sauna. A 63 year old man without previously recognized liver and other systemic disease was admitted for loss of consciousness and impaired liver function after sauna. Despite intensive supportive care, ALF developed. Liver transplantation was planned but the patient died on the sixth day of hospitalization. Non-exertional heatstroke induced ALF is a rare and serious condition. ALF caused by non-exertional heatstroke which requires liver transplantation for definitive solution should be kept in mind in early period.

  14. Acute kidney injury in acute on chronic liver failure.

    Science.gov (United States)

    Maiwall, Rakhi; Sarin, S K; Moreau, Richard

    2016-03-01

    Acute on chronic liver failure (ACLF) is a distinct clinical entity; however, there is still debate in the way it is defined in the East as compared to the West, especially with respect to incorporation of kidney dysfunction or failure in the definition of ACLF. Kidney dysfunction is defined as serum creatinine between 1.5 and 1.9 mg/dl and kidney failure as serum creatinine of more than 2 mg/dl or requirement of renal replacement therapy according to the EASL-CLIF Consortium. Kidney dysfunction or failure is universally present in patients with ACLF according to the definition by the EASL-CLIF Consortium while on the contrary the APASL definition of ACLF does not incorporate kidney dysfunction or failure in its definition. Recently, both the diagnosis and management of renal failure in patients with cirrhosis has changed with the advent of the acute kidney injury (AKI) criteria defined as an abrupt decline in renal functions, characterized by an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or an increase of more than 50 % from baseline, which is known or presumed to have occurred in the previous 7 days. Further, recent studies in patients with cirrhosis have shown the utility of biomarkers for the diagnosis of AKI. The present review covers the pathogenetic mechanisms, diagnosis, prognosis as well as management of AKI in patients with ACLF from both a Western as well as an Eastern perspective. The review identifies an unmet need to diagnose AKI and prevent this ominous complication in patients with ACLF.

  15. Auxiliary partial liver transplantation for acute liver failure using "high risk" grafts: Case report.

    Science.gov (United States)

    Duan, Wei-Dong; Wang, Xi-Tao; Wang, Hong-Guang; Ji, Wen-Bin; Li, Hao; Dong, Jia-Hong

    2016-02-07

    Acute liver failure (ALF) is a reversible disorder that is associated with an abrupt loss of hepatic mass, rapidly progressive encephalopathy and devastating complications. Despite its high mortality, an emergency liver transplantation nowadays forms an integral part in ALF management and has substantially improved the outcomes of ALF. Here, we report the case of a 32-year-old female patient who was admitted with grade IV hepatic encephalopathy (coma) following drug-induced ALF. We performed an emergency auxiliary partial orthotopic liver transplantation with a "high risk" graft (liver macrovesicular steatosis approximately 40%) from a living donor. The patient was discharged on postoperative day 57 with normal liver function. Weaning from immunosuppression was achieved 9 mo after transplantation. A follow-up using CT scan showed a remarkable increase in native liver volume and gradual loss of the graft. More than 6 years after the transplantation, the female now has a 4-year-old child and has returned to work full-time without any neurological sequelae.

  16. 题目:CYP450代谢酶和一些抗氧化信号参与调控了绿原酸抑制对乙酰氨基酚的肝毒性%Chlorogenic acid prevents acetaminophen-induced liver injury:the involvement of CYP450 metabolic enzymes and some antioxidant signals

    Institute of Scientific and Technical Information of China (English)

    Chun PANG; Yu-chen SHENG; Ping JIANG; Hai WEI; Li-li JI

    2015-01-01

    目的:本研究旨在观察绿原酸对乙酰氨基酚诱导肝损伤的解毒作用及其机理。创新点:发现CYP450代谢酶和一些重要的抗氧化信号分子(如Prx家族蛋白等)参与调控了绿原酸抑制对乙酰氨基酚的肝毒性。方法:检测小鼠血清转氨酶含量,检测体外 CYP2E1、CYP3A4和CYP1A2酶活性,检测肝组织中丙二醛(MDA)、谷胱甘肽(GSH)和活性氧(ROS)含量,用实时聚合酶链反应(real-time PCR)检测肝组织中Prx1-6、Ephx2、Polr2k、Fmo5、Nrf2等的mRNA表达情况。结论:绿原酸可以明显抑制对乙酰氨基酚造成的急性肝损伤。给药组小鼠血清中的转氨酶与模型组相比均有显著下降,绿原酸在体外可以微弱抑制CYP2E1和CYP1A2代谢酶的活性,通过MDA、GSH和 ROS分析发现绿原酸可以抑制对乙酰氨基酚造成的氧化应激损伤。通过real-time PCR分析发现对乙酰氨基酚降低了抗氧化酶 Prx家族、Ephx2、Polr2k和 Nrf2的基因表达,而绿原酸可以逆转对乙酰氨基酚降低的这些基因的表达。%Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cel viability induced by AP in L-02 celsin vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST)in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin

  17. Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder

    Institute of Scientific and Technical Information of China (English)

    Miguel Bispo; Ana Valente; Rosário Maldonado; Rui Palma; Helena Glória; Jo(a)o Nóbrega; Paula Alexandrino

    2009-01-01

    Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

  18. [Therapy with opioids in liver or renal failure].

    Science.gov (United States)

    Tegeder, I; Geisslinger, G; Lötsch, J

    1999-06-11

    In patients with renal or hepatic failure, the pharmacokinetics of opioids may be affected in several ways, leading to the necessity to correct the dose. The liver is the major site for biotransformation of most opioids. The major metabolic pathway is oxidation. Exceptions to this are morphine and buprenorphine, which undergo primarily glucuronidation, and remifentanil which is cleared by esther hydrolysis. The hydrophilic metabolites are predominantly excreted by the kidneys and may accumulate in patients with renal insufficiency. Some metabolites such as morphine-6-glucuronide (M6G) or normeperidine are active opioid agonists. With high concentrations they may cause narcotic effects or respiratory depression. In addition, special risks are known for normepridine that has been shown to exert neurotoxic effects with the risk of seizures. Few cases of respiratory depression following the administration of codeine, dihydrocodeine and tramdol have been reported. The elimination half-life of these drugs was prolonged. Lastly, the disposition of methadone, buprenorphine, fentanyl, sufentanyl and remifentanil appears to be unaffected in renal failure. In patients with hepatic cirrhosis it has been shown that oxidation of opioids is reduced, resulting in a decreased drug clearance (meperidine, propoxyphene, pentazocine, tramadol and alfentanil) and increased oral bioavailability due to reduced first-pass metabolism (meperidine, propoxyphene, pentazocine, dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, the clearance of morphine was found to be decreased and its oral bioavailability increased. The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administrations. As for patients with renal failure, special risks are known for meperidine with potential accumulation of normeperidine, which can cause seizures, and for propoxyphene for which several cases of hepatotoxicity have

  19. Prometheus system: a technological support in liver failure.

    Science.gov (United States)

    Santoro, A; Faenza, S; Mancini, E; Ferramosca, E; Grammatico, F; Zucchelli, A; Facchini, M G; Pinna, A D

    2006-05-01

    The Prometheus system is a plasma filtration treatment coupling adsorption and hemodialysis (FPSA) aimed to blood purification in liver failure. After separation through an albumin-permeable membrane, plasma enters a secondary circuit where protein-bound toxic substances are removed by two adsorbers; p01, a neutral resin, and p02, an anion exchanger. Plasma is then returned to the venous line, where a high-flux hemodialyzer removes water-soluble substances. We used the Prometheus system in 12 patients with acute or acute-on-chronic liver insufficiency: eight cirrhosis, one posttransplant dysfunction, and three secondary liver insult (two cardiogenic shock and one rhabdomyolysis). All patients were severely hyperbilirubinemic, hypercholemic, and hyperammonemic. Twenty-eight sessions each lasting 340 +/- 40 minutes were performed (2.5/patient). The mean total bilirubin decreased from 33.6 +/- 20 to 22.2 +/- 13.6 mg/dL (P Prometheus, based on FPSA, produced high clearance for protein-bound and water soluble markers, which resulted in high treatment efficacy.

  20. TECA hybrid artificial liver support system in treatment of acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Yi-Long Xue; Xin-Cui; Da-Guang Zhong; Zuo-Yun Zhang; Zhi-Qiang Huang; Shi-Feng Zhao; Yun-Luo; Xin-Jian Li; Zhong-Ping Duan; Xiao-Ping Chen; Wen-Ge Li; Xiao-Qiang Huang; Yan-Ling Li

    2001-01-01

    AIM: To assess the efficacy and safety of TECA type hybrid artificial liver support system (TECA-HALSS) in providing liver function of detoxification, metabolism and physiology by treating the patients with acute liver failure (ALF). METHODS: The porcine liver cells (1 - 2 ) x 1010 were separated from the Chinese small swine and cultured in the bioreactor of TECA-BALSS at 37.0°C and circulated through the outer space of the hollow fiber tubes in BALSS. The six liver failure patients with various degree of hepatic coma were treated by TECA-HALSS and with conventional medicines. The venous plasma of the patients was separated by a plasma separator and treated by charcoal adsorbent or plasma exchange. The plasma circulated through the inner space of the hollow fiber tubes of BALSS and mixed with the patients' blood cells and flew back to their blood circulation. Some small molecular weight substances were exchanged between theplasma and porcine liver cells. Each treatment lasted 6.0-7.0 h.Physiological and biochemical parameters were measured before, during and after the treatment. RESULTS: The average of porcine liver cells was (1.0- 3.0)x 1010 obtained from each swine liver using our modified enzymatic digestion method. The survival rate of the cells was 85% - 93% by tnypan blue stain and AO/PI fluorescent stain. After cultured in TECA-BALSS bioreactor for 6 h, the survival rate of cells still remained 70% - 85%. At the end of TECA-HALSS treatment, the levels of plasma NH3, ALT, TB and DB were significantly decreased. The patients who were in the state of drowsiness or coma before the treatment improved their appetite significantly and regained consciousness, some patients resumed light physical work on a short period after the treatment. One to two days after the treatment, the ratio of PTA increased warkedly. During the treatment, the heart rates, blood pressure, respiration condition and serum electrolytes (K+, Na+ and Cl) were stable without thrombosis and

  1. Pathological changes of the livers from 39 patients with hepatic failure

    Institute of Scientific and Technical Information of China (English)

    崇雨田

    2006-01-01

    Objective To explore the pathological changes of the livers from hepatic failure (HF) patients and its association with clinical disease stages. Methods Thirtynine patients with liver failure caused by HBV infections were investigated, and none accompanied with hepatocellular carcinoma. The sections of tissue were taken from the liver after liver transplantation and stained with hematoxylin -eosin (H&E) or RT (reticular fiber) staining. The pathological features were analyzed and compared between the clinical and pathological diagnosis.

  2. Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Wang, Yanzhong; Maggs, James

    2016-01-01

    BACKGROUND: Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver ...... in paracetamol-induced acute liver failure require re-evaluation. FUNDING: Foundation for Liver Research. Copyright © 2016 Elsevier Ltd. All rights reserved....... normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate. FINDINGS: We developed and validated new high-performance statistical models to support decision making in patients with paracetamol...

  3. What factors determine the severity of hepatitis A-related acute liver failure?

    Science.gov (United States)

    Ajmera, V.; Xia, G.; Vaughan, G.; Forbi, J. C.; Ganova-Raeva, L. M.; Khudyakov, Y.; Opio, C. K.; Taylor, R.; Restrepo, R.; Munoz, S.; Fontana, R. J.; Lee, W. M.

    2016-01-01

    SUMMARY The reason(s) that hepatitis A virus (HAV) infection may progress infrequently to acute liver failure are poorly understood. We examined host and viral factors in 29 consecutive adult patients with HAV-associated acute liver failure enrolled at 10 sites participating in the US ALF Study Group. Eighteen of twenty-four acute liver failure sera were PCR positive while six had no detectable virus. HAV genotype was determined using phylogenetic analysis and the full-length genome sequences of the HAV from a cute liver failure sera were compared to those from self-limited acute HAV cases selected from the CDC database. We found that rates of nucleotide substitution did not vary significantly between the liver failure and non-liver failure cases and there was no significant variation in amino acid sequences between the two groups. Four of 18 HAV isolates were subgenotype IB, acquired from the same study site over a 3.5-year period. Sub-genotype IB was found more frequently among acute liver failure cases compared to the non-liver failure cases (chi-square test, P viral clearance and its association with poor outcomes in acute liver failure as well as the finding of familial cases imply a possible host genetic predisposition that contributes to a fulminant course. Recurrent cases of the rare subgenotype IB over several years at a single centre imply a community reservoir of infection and possible increased pathogenicity of certain infrequent viral genotypes. PMID:21143345

  4. DRESS syndrome secondary to ibuprofen as a cause of hyperacute liver failure

    Directory of Open Access Journals (Sweden)

    Valentín Roales-Gómez

    2014-08-01

    Full Text Available Acute liver failure has a high mortality and its most frequent cause in Spain is viral infection. In this article, we present a case of fulminant liver failure. The failure is secondary to an idiosyncratic reaction to ibuprofen, an entity included in the DRESS syndrome. This syndrome plays a key role in the differential diagnosis of acute liver failure, since its unfortunate course often requires liver transplantation as the only useful therapeutic weapon. This case illustrates the need for an efficient coordination between hospitals as a key factor for improving the prognosis.

  5. Acute Liver Failure Associated with Levetiracetam and Lacosamide Combination Treatment for Unspecified Epileptic Disorder

    Directory of Open Access Journals (Sweden)

    Ylse Gutiérrez-Grobe

    2013-01-01

    Full Text Available Background and Aim. Levetiracetam is a second-generation antiepileptic drug. It is approved as an adjunctive treatment of partial onset seizures with or without secondary generalization. It is considered safe with less than 1% of patients with transient elevations of liver enzymes. Methods. We report a case of acute liver failure secondary to Levetiracetam in combination with Lacosamide documented with a liver biopsy. Results. Liver biopsy demonstrated acute liver injury with a predominant submassive necrosis pattern and features of a drug-induced hepatitis. Conclusions. This is the first published case of acute liver failure due to antiepileptic therapy with Levetiracetam in combination with Lacosamide.

  6. Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

    Science.gov (United States)

    Ohno, Yukako; Hanawa, Haruo; Jiao, Shuang; Hayashi, Yuka; Yoshida, Kaori; Suzuki, Tomoyasu; Kashimura, Takeshi; Obata, Hiroaki; Tanaka, Komei; Watanabe, Tohru; Minamino, Tohru

    2015-01-01

    Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

  7. Acute hepatic failure and multi-system organ failure secondary to replacement of the liver with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Culleton Bruce

    2005-06-01

    Full Text Available Abstract Background Metastatic malignant melanoma to the liver resulting in fulminant hepatic failure is a rare occurrence. Case presentation A 46 year old man presented to hospital with massive hepatomegaly, elevated liver enzymes and increased lactate three weeks following resection of a malignant melanoma from his shoulder (Clark level 5. Initially stable, he decompensated 24 to 48 hours subsequent to presentation with respiratory failure requiring mechanical ventilation, distributive shock requiring high dose vasopressor infusion, coagulopathy refractory to plasma infusion, progressive rise in liver enzymes and severe metabolic abnormalities including hyperkalemia, acidosis, hyperphosphatemia, hyperuricemia and hypocalcemia. Refractory to aggressive physiologic support he received palliation. Autopsy revealed >80% liver infiltration by metastatic malignant melanoma. Conclusion We report a case of fulminant hepatic failure secondary to metastatic malignant melanoma infiltration of the liver.

  8. Artificial liver support system combined with liver transplantation in the treatment of patients with acute-on-chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Xiao Xu

    Full Text Available BACKGROUND: The search for a strategy to provide temporary liver support and salvage the patients with acute-on-chronic liver failure (ACLF remains an important issue. This study was designed to evaluate the experience in artificial liver support system (ALSS combined with liver transplantation (LT in the treatment of ACLF. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and seventy one patients with HBV related ACLF undergoing LT between January 2001 and December 2009 were included. Of the 171 patients, 115 received 247 sessions of plasma exchange-centered ALSS treatment prior to LT (ALSS-LT group and the other 56 received emergency LT (LT group. The MELD score were 31±6 and 30±7 in ALSS-LT group and LT group. ALSS treatment resulted in improvement of liver function and better tolerance to LT. The average level of serum total bilirubin before LT was lower than that before the first time of ALSS treatment. The median waiting time for a donor liver was 12 days (2-226 days from the first run of ALSS treatment to LT. Compared to LT group, the beneficial influences of ALSS on intraoperative blood loss and endotracheal intubation time were also observed in ALSS-LT group. The 1-year and 5-year survival rates in the ALSS-LT group and LT group were 79.2% and 83%, 69.7% and 78.6%. CONCLUSIONS/SIGNIFICANCE: Plasma exchange-centered ALSS is beneficial in salvaging patients with ACLF when a donor liver is not available. The consequential LT is the fundamental treatment modality to rescue these patients and lead to a similar survival rate as those patients receiving emergency transplantation.

  9. Desferrioxamine attenuates minor lung injury following surgical acute liver failure.

    Science.gov (United States)

    Kostopanagiotou, G G; Kalimeris, K A; Arkadopoulos, N P; Pafiti, A; Panagopoulos, D; Smyrniotis, V; Vlahakos, D; Routsi, C; Lekka, M E; Nakos, G

    2009-06-01

    Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.

  10. Acute liver failure in pregnancy: Causative and prognostic factors

    Directory of Open Access Journals (Sweden)

    Shweta Sahai

    2015-01-01

    Full Text Available Background/Aims: Acute liver failure (ALF in pregnancy is often associated with a poor prognosis. In this single-center observational study we aim to study the incidence, causes, and factors affecting mortality in pregnant women with ALF. Patients and Methods: Sixty-eight pregnant women reporting with clinical features of liver dysfunction were enrolled as "cases." Their clinical course was followed and laboratory studies were performed. The presence of ALF was defined as the appearance of encephalopathy. The results were compared with a "control" group of 16 nonpregnant women presenting with similar complaints. The cases were further subdivided into two groups of "survivors" and "nonsurvivors" and were compared to find out the factors that contribute to mortality. Results: ALF was seen in significantly more number of pregnant women than the controls (P = 0.0019. The mortality rate was also significantly higher (P = 0.0287. Hepatitis E virus (HEV caused jaundice in a higher number of pregnant women (P < 0.001. It also caused ALF in majority (70.3% of pregnant women, but HEV infection was comparable between the survivors and nonsurvivors (P = 0.0668, hence could not be correlated with mortality. Conclusions: Pregnant women appear to be more susceptible for HEV infection and development of ALF. The mortality of jaundiced pregnant women increased significantly with appearance of ALF, higher bilirubin, lower platelet count, higher international normalized ratio, and spontaneous delivery.

  11. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation.

    Science.gov (United States)

    Rodrigo, L; de Francisco, R; Pérez-Pariente, J M; Cadahia, V; Tojo, R; Rodriguez, M; Lucena, Ma I; Andrade, R J

    2002-11-01

    We present the case of a 63-year-old woman who had undergone 7 months of treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The patient was admitted to our unit with a clinical picture of progressive jaundice over 3 weeks. Clinical and analytical studies revealed acute liver failure, this being confirmed by liver biopsy, which showed submassive necrosis. Serological tests for different viral agents causing hepatitis were all negative. In addition, she presented a picture of severe haemolytic anaemia resistant to several treatments and needed multiple transfusions. Twenty-three days after admission, the patient presented hepatic encephalopathy and received an orthotopic liver transplant on day 25. The evolution after transplantation was good and the patient continues in good health with no evidence of haemolysis almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our knowledge the occurrence of haemolytic anaemia has not been related to this drug previously. For these reasons, Nimesulide has been restricted or removed from the market in several countries in recent months.

  12. Alginate microencapsulated hepatocytes optimised for transplantation in acute liver failure.

    Directory of Open Access Journals (Sweden)

    Suttiruk Jitraruch

    Full Text Available BACKGROUND AND AIM: Intraperitoneal transplantation of alginate-microencapsulated human hepatocytes is an attractive option for the management of acute liver failure (ALF providing short-term support to allow native liver regeneration. The main aim of this study was to establish an optimised protocol for production of alginate-encapsulated human hepatocytes and evaluate their suitability for clinical use. METHODS: Human hepatocyte microbeads (HMBs were prepared using sterile GMP grade materials. We determined physical stability, cell viability, and hepatocyte metabolic function of HMBs using different polymerisation times and cell densities. The immune activation of peripheral blood mononuclear cells (PBMCs after co-culture with HMBs was studied. Rats with ALF induced by galactosamine were transplanted intraperitoneally with rat hepatocyte microbeads (RMBs produced using a similar optimised protocol. Survival rate and biochemical profiles were determined. Retrieved microbeads were evaluated for morphology and functionality. RESULTS: The optimised HMBs were of uniform size (583.5±3.3 µm and mechanically stable using 15 min polymerisation time compared to 10 min and 20 min (p<0.001. 3D confocal microscopy images demonstrated that hepatocytes with similar cell viability were evenly distributed within HMBs. Cell density of 3.5×10(6 cells/ml provided the highest viability. HMBs incubated in human ascitic fluid showed better cell viability and function than controls. There was no significant activation of PBMCs co-cultured with empty or hepatocyte microbeads, compared to PBMCs alone. Intraperitoneal transplantation of RMBs was safe and significantly improved the severity of liver damage compared to control groups (empty microbeads and medium alone; p<0.01. Retrieved RMBs were intact and free of immune cell adherence and contained viable hepatocytes with preserved function. CONCLUSION: An optimised protocol to produce GMP grade alginate

  13. Predictive factors for liver dysfunction and failure after hepatectomy: Analysis of 467 patients with hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Guangjin Du; Liqun Wu; Chengzhan Zhu; Rong Ye; Xin Yi

    2012-01-01

    Objective: The aim of our study was to analyze hepatic dysfunction and failure after hepatocellular carcinoma (HCC) resection and relationship of clinical and pathological factors.Methods: Clinical and pathological data of 467 HCC patients was retrospectively reviewed, who underwent liver resection from January 2002 to December 2008 in the Affiliated Hospital of Medical College, Qingdao University, and the post-resectional liver dysfunction and failure risk factors were analyzed by univariate and multivariate analysis.Results: The morbidity of post-resectional liver dysfunction and failure was 1.7% and 2.1%.The post-resectional liver dysfunction and failure after HCC hepatectomy into the statistical analysis: univariate analysis revealed preoperative platelet level ( 64 U/L), Child-Pugh classification (B), MELD score (≥ 9), intraoperative bleeding (≥ 1000 mL), blood transfusion were positive factors, multivariate analysis (Logistic) revealed that preoperative platelet level (0.983, 95% CI = 0.971-0.995) and intraoperative blood transfusion (3.145, 95% CI = 1.027-12.028) were independent risk factors for post-resectional liver dysfunction and failure.Conclusion: Prevented liver failure and liver dysfunction occurring after liver resection, it is the key to accurate preoperative assessment of liver function and the patient's reserved liver functional, precise hepatectomy and reasonable blockage of hepatic inflow.

  14. Serum thymosin β4 levels in patients with hepatitis B virus-related liver failure

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To investigate whether serum thymosinβ4 can provide diagnostic or prognostic information in liver failure patients caused by chronic hepatitis B virus(HBV) infection. METHODS:Serum thymosinβ4 levels were measured in 30 patients with acute-on-chronic liver failure(ACLF), 31 patients with chronic liver failure(CLF),30 patients with compensated liver cirrhosis(CR)and 32 patients with chronic hepatitis B and 30 healthy controls.Serum thymosinβ4 levels were measured by enzyme-linked immunosorbent assay and C...

  15. Risk factors of acute renal failure after liver transplantation.

    Science.gov (United States)

    Cabezuelo, J B; Ramírez, P; Ríos, A; Acosta, F; Torres, D; Sansano, T; Pons, J A; Bru, M; Montoya, M; Bueno, F S; Robles, R; Parrilla, P

    2006-03-01

    The objective of this study was to determine the risk factors of postoperative acute renal failure (ARF) in orthotopic liver transplantation (OLT). We reviewed 184 consecutive OLT. Postoperative ARF was defined as a persistent rise of 50% increase or more of the S-creatinine (S-Cr). The patients were classified as early postoperative ARF (E-ARF) (first week) and late postoperative ARF (L-ARF) (second to fourth week). Preoperative variables were age, sex, comorbidity, indication for OLT, Child-Pugh stage, united network for organ sharing status, analysis of the blood and urine, and donor's data. Intraoperative variables were systolic arterial pressure, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance index. Surgical technique, number of blood products transfused, need for adrenergic agonist drugs, and intraoperative complications were also important. Postoperative variables were duration of stay in the intensive care unit, time on mechanic ventilation, liver graft dysfunction, need for adrenergic agonist drugs, units of blood products infused, episodes of acute rejection, re-operations, and bacterial infections. Firstly we carried out a univariate statistical analysis, and secondly a logistic regression analysis. The risk factors for E-ARF were: pretransplant ARF (odds ratio (OR)=10.2, P=0.025), S-albumin (OR=0.3, P=0.001), duration of treatment with dopamine (OR=1.6, P=0.001), and grade II-IV dysfunction of the liver graft (OR=5.6, P=0.002). The risk factors for L-ARF were: re-operation (OR=3.1, P=0.013) and bacterial infection (OR=2.9, P=0.017). The development of E-ARF is influenced by preoperative factors such as ARF and hypoalbuminemia, as well as postoperative factors such as liver dysfunction and prolonged treatment with dopamine. The predicting factors of L-ARF differ from E-ARF and correspond to postoperative causes such as bacterial infection and surgical re-operation.

  16. A Liver-centric Multiscale Modeling Framework for Xenobiotics

    Science.gov (United States)

    We describe a multi-scale framework for modeling acetaminophen-induced liver toxicity. Acetaminophen is a widely used analgesic. Overdose of acetaminophen can result in liver injury via its biotransformation into toxic product, which further induce massive necrosis. Our study foc...

  17. Clinical analysis and prognostic judgment of artificial extracorporeal liver support therapy for pediatric acute liver failure

    Directory of Open Access Journals (Sweden)

    ZHANG Zhen

    2015-08-01

    Full Text Available Objective To observe the clinical efficacy of artificial extracorporeal liver support therapy in the treatment of pediatric acute liver failure (PALF and to analyze the associated prognostic factors. Methods The clinical records of 23 patients with PALF treated from January 2012 to February 2015 in the Pediatric Intensive Care Unit of the First Hospital of Jilin University were analyzed retrospectively. After three-month follow-up, 15 patients survived (survival group, n=15, while 8 patients died (death group, n=8. The changes in biomarkers of liver function and coagulation function after treatment were evaluated within groups. At the same time, the above parameters and Model for End-Stage Liver Disease (MELD score before treatment were compared between the two groups. The efficacy of artificial extracorporeal liver support therapy was analyzed, and the prognostic factors were reviewed. The t test was applied in the comparison of continuous data. Results In the survival group, the levels of serum alanine aminotransferase (ALT, total bilirubin (TBil, ammonia, and lactic acid were significantly reduced after treatment (t=8.812, 6.243, 8.431, and 6.721, respectively; all P<0.01. However, in the death group, only ALT level was significantly reduced after treatment (t=2.532, P<0.05. Compared with the levels before treatment, the levels of prothrombin time (PT, prothrombin time activity (PTA, and international normalized ratio (INR were significantly improved after treatment (t=6.256, -2.738, and 6.711, respectively; all P<0.05. Before treatment, compared with the survival group, patients in the death group presented significantly lower level of ALT (t=6.283,P<0.01, significantly higher level of TBil (t=-3.938, P=0.001, significantly longer PT (t=-2.394, P=0.026, and significantly higher MELD score (t=-6.239, P<0.01. Conclusion Artificial extracorporeal liver support therapy is an effective way of treating PALF. Once patients with high ALT level

  18. Adrenal Insufficiency as a Cause of Acute Liver Failure: A Case Report

    Directory of Open Access Journals (Sweden)

    Jamshid Vafaeimanesh

    2013-01-01

    Full Text Available Introduction. Many diseases and conditions can contribute to elevated liver enzymes. Common causes include viral and autoimmune hepatitis, fatty liver, and bile duct diseases, but, in uncommon cases like liver involvement in endocrine disorders, liver failure is also seen. Adrenal insufficiency is the rarest endocrine disorder complicating the liver. In the previously reported cases of adrenal insufficiency, mild liver enzymes elevation was seen but we report a case with severe elevated liver enzymes and liver failure due to adrenal insufficiency. Based on our knowledge, this is the first report in this field. Case Report. A 39-year-old woman was referred to emergency ward due to drowsiness and severe fatigue. Her laboratory tests revealed prothrombin time: 21 sec, alanine aminotransferase (ALT: 2339 IU/L, aspartate aminotransferase (AST: 2002 IU/L, and ALP: 90 IU/L. No common cause of liver involvement was discovered, and eventually, with diagnosis of adrenal insufficiency and corticosteroid therapy, liver enzymes and function became normal. Finally, the patient was discharged with good general condition. Conclusion. With this report, we emphasize adrenal insufficiency (primary or secondary as a reason of liver involvement in unexplainable cases and recommend that any increase in the liver enzymes, even liver failure, in these patients should be observed.

  19. TRANSPLANTATION OF HEPATOCYTES AS THE METHOD OF TREATMENT OF LIVER FAILURE: EXPERIMENTAL AND CLINICAL EXPERIENCE

    Directory of Open Access Journals (Sweden)

    M. Y. Shagidulin

    2010-01-01

    Full Text Available For correction and treatment of liver failure before liver transplantation were proposed severe methods such as: extracorporal devices, transplantation of hepatocytes and implanted tissue-engineering units. The function of healthy hepatocytes presumes to stabilize the state of patients with chronic liver diseases and to wait a donor organ transplantation. In this review the results of experimental and clinical therapy of liver diseases by method of hepatocyte transplantation were summarized. 

  20. High-volume plasma exchange in patients with acute liver failure

    DEFF Research Database (Denmark)

    Larsen, Fin Stolze; Schmidt, Lars Ebbe; Bernsmeier, Christine

    2016-01-01

    BACKGROUND & AIMS: Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15...

  1. Propylthiouracil-induced liver failure and artificial liver support systems: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Wu DB

    2017-01-01

    Full Text Available Dong-Bo Wu,1,2 En-Qiang Chen,1,2 Lang Bai,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, 2Division of Molecular Biology of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, People’s Republic of China Background: Antithyroid drugs carry a potential risk of hepatotoxicity. Propylthiouracil (PTU is commonly prescribed for patients with hyperthyroidism. PTU, however, can induce liver injury, ranging from mild asymptomatic elevation of aminotransferases to acute liver failure (ALF.Case presentation: This case reports on a 16-year-old Chinese girl with hyperthyroidism, who was admitted to our hospital for jaundice, nausea, and fatigue associated with severe hyperbilirubinemia and coagulopathy. She had been prescribed PTU 5 months earlier. There was no history of hypersensitivity to drugs, viral liver diseases, blood transfusion, or surgery. On the basis of her symptoms and the clinical data, she was diagnosed with PTU-induced ALF. Due to the limited number of available donor organs for liver transplantation, she was started on treatment with artificial liver support system (ALSS. After four sessions of ALSS, her clinical signs and symptoms were found to be markedly improved, and she was discharged 25 days after admission. Four months later, her liver function normalized.Conclusion: Although PTU-induced liver failure is rare in clinical practice, liver function should be appropriately monitored during treatment with PTU. PTU-induced ALF in this patient was successfully managed with an ALSS, suggesting that the latter may be an alternative to liver transplantation. Keywords: propylthiouracil, liver injury, acute liver failure, artificial liver support systems 

  2. Preoperative prediction and prevention of intraoperative acute liver failure after major liver resection for metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    A. D. Kaprin

    2016-01-01

    Full Text Available Objective: improve the results of treatment of patients with metastatic cancer of liver by reducing the risk of post-resection liver failure based on the assessment of liver functional reserve.Materials and methods. The study included 2 independent samples of patients underwent surgery for liver metastases in the department of abdominal oncology at the P. A. Herzen Moscow Oncological Research Institute. Group 1 included 47 patients: in addition to the standard treatment algorithm they underwent 13C methacetin breath test and dynamic scintigraphy of liver in the preoperative stage. Patients from the group 2 (n = 30 underwent standard clinical and laboratory examination, without preoperative evaluation of liver functional reserves; the level of total bilirubin, albumin and prothrombin time showed no decrease in liver function. Post-resection liver failure was established based on 50/50 criterion when evaluated on the 5th postoperative day.Results. The analysis of operational characteristics of functional tests showed absolute sensitivity of 13C methacetin breath test (SE ≥ 100 % and negative predictive value (–VP ≥ 100 % in case of integrated application of 2 diagnostic methods. An incidence of post-resection acute liver failure in the study group was significantly 2.2-fold lower than in the control group – 10.6 % and 23.3 %, respectively (p < 0.001.Conclusion. Combination of preoperative dynamic scintigraphy of liver with 13C methacetin breath test allows to perform comprehensive assessment of liver functional reserves, and it can greatly improve preoperative assessment and postoperative results of anatomic resections in patients with liver metastases.

  3. Radiographically occult intrasinusoidal liver metastases leading to hepatic failure in a case of breast cancer.

    Science.gov (United States)

    Gulia, Seema; Khurana, Sachin; Shet, Tanuja; Gupta, Sudeep

    2016-02-15

    The liver is one of the commonest sites of metastatic involvement in breast cancer, usually evident as focal lesions on imaging tests. Rarely, the pattern of metastatic spread is so diffuse that it remains radiologically occult. Such patients usually present with signs of hepatic insufficiency without any focal lesions on liver imaging. In such cases, liver biopsy is required to make a definitive diagnosis. We report a case of a 56-year-old postmenopausal woman with metastatic breast cancer who presented with subacute progressive liver failure. Repeated imaging of the liver was normal or non-descript. Liver biopsy finally established the diagnosis of intrasinusoidal metastases from breast cancer.

  4. Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Darin S Krygier; Urs P Steinbrecher; Martin Petric; Siegfried R Erb; Stephen W Chung; Charles H Scudamore; Andrzej K Buczkowski; Eric M Yoshida

    2009-01-01

    Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported,mainly in children.Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation.We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation.This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation.This case suggests that Parvovirus B19 induced liver disease can affect adults,can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.

  5. Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure.

    Science.gov (United States)

    Kuijk, Ewart W; Rasmussen, Shauna; Blokzijl, Francis; Huch, Meritxell; Gehart, Helmuth; Toonen, Pim; Begthel, Harry; Clevers, Hans; Geurts, Aron M; Cuppen, Edwin

    2016-02-26

    The rat is an important model for liver regeneration. However, there is no in vitro culture system that can capture the massive proliferation that can be observed after partial hepatectomy in rats. We here describe the generation of rat liver stem cell lines. Rat liver stem cells, which grow as cystic organoids, were characterized by high expression of the stem cell marker Lgr5, by the expression of liver progenitor and duct markers, and by low expression of hepatocyte markers, oval cell markers, and stellate cell markers. Prolonged cultures of rat liver organoids depended on high levels of WNT-signalling and the inhibition of BMP-signaling. Upon transplantation of clonal lines to a Fah(-/-) Il2rg(-/-) rat model of liver failure, the rat liver stem cells engrafted into the host liver where they differentiated into areas with FAH and Albumin positive hepatocytes. Rat liver stem cell lines hold potential as consistent reliable cell sources for pharmacological, toxicological or metabolic studies. In addition, rat liver stem cell lines may contribute to the development of regenerative medicine in liver disease. To our knowledge, the here described liver stem cell lines represent the first organoid culture system in the rat.

  6. The protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    Nnodim Johnkennedy; Emejulu Adamma

    2011-01-01

    Objective: To evaluate the protective effect of leaf extract of Gongronema latifolium (G. latifolium) against acute acetaminophen induced hepatic toxicity in Wistar rats. Methods:Thirty six Wistar rats were divided into 6 groups with 6 rats in each group. Animals in group 1 and 2 were administered with 600 mg/kg b.w. of acetaminophen only and acetaminophen plus 100 mg/kg b.w. of caffeine by oral gavages, respectively. Experimental groups 3 and 4 were treated as in group 1 but in addition received 200 and 400 mg/kg b.w., respectively of the leaf extract of G. latifolium by oral gavages. The experimental groups 5 and 6 were treated as in group 2 and in addition received 200 and 400 mg/kg b.w. of leaf extract of G. latifolium, respectively. The treatment lasted for 14 days. Results: The results obtained showed that the serum glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) and alkaline phosphatase (ALP) levels had a greater increase in group 2 than in group 1 but dropped marginally in groups 3 and 4. However, in groups 5 and 6, AST, ALT and ALP were significantly reduced (P<0.05). Similarly, serum protein levels were significantly increased in groups 3, 4, 5 and 6 when compared with group 1 and 2. Conclusions: It can be concluded that extract of G. latifolium offers protection against acetaminophen and caffeinated acetaminophen toxicity in Wistar rats.

  7. A case of acetaminophen-induced acute tubulointerstitial nephritis in adult.

    Science.gov (United States)

    Inoue, Dan; Usui, Ryosuke; Nitta, Kosaku; Koike, Minako

    2017-08-11

    We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi-pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN.

  8. Effect of a bioflavonoid dietary supplement on acetaminophen-induced oxidative injury to feline erythrocytes.

    Science.gov (United States)

    Allison, R W; Lassen, E D; Burkhard, M J; Lappin, M R

    2000-10-15

    To determine the effect of a commercial bioflavonoid antioxidant on acetaminophen-induced oxidative injury to feline erythrocytes. Randomized controlled study. 45 healthy age-matched cats. Cats were assigned to 3 experimental groups. Groups 1 and 3 received a bioflavonoid antioxidant (10 mg/d) orally for 2 weeks. Groups 2 and 3 received an oxidative challenge with acetaminophen (90 mg/kg [41 mg/lb] of body weight, PO) on day 7. Packed cell volume, percentage of erythrocytes with Heinz bodies, blood methemoglobin concentration, and blood reduced and oxidized glutathione concentrations were determined at various times during the 2-week study period. Adverse effects were not associated with bioflavonoid antioxidant administration alone. Acetaminophen administration resulted in a significant increase in methemoglobin concentration in groups 2 and 3; differences were not detected between these groups. Heinz body concentrations in groups 2 and 3 increased after acetaminophen administration; however, the increase in cats that received the antioxidant was significantly less than in group-2 cats. Total blood glutathione concentrations did not change significantly in groups 2 and 3 after acetaminophen administration; however, ratio of reduced to oxidized glutathione concentration increased significantly after administration in group-2 cats, compared with group-3 cats. Oral administration of bioflavonoid antioxidants to cats at risk for oxidative stress may have a beneficial effect on their ability to resist oxidative injury to erythrocytes.

  9. A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review

    Directory of Open Access Journals (Sweden)

    G. Kneiseler

    2010-02-01

    Full Text Available The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter β-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure.

  10. Plasma ghrelin concentrations, food intake, and anorexia in liver failure.

    Science.gov (United States)

    Marchesini, Giulio; Bianchi, Giampaolo; Lucidi, Paola; Villanova, Nicola; Zoli, Marco; De Feo, Pierpaolo

    2004-05-01

    Ghrelin is related to feeding behavior and nutrition in several physiological and pathological conditions. We tested the hypothesis that the anorexia and the decreased food intake of advanced liver failure might be associated with hyperghrelinemia. Fasting ghrelin was measured in 43 cirrhotic patients, food intake was self-assessed using the Corli score and a 3-d dietary record (n = 25), and anorexia/hunger was tested by a Likert scale. Fifty healthy subjects, matched for age and body mass index, served as controls. Ghrelin levels were not systematically increased in cirrhosis (414 +/- 164 vs. 398 +/- 142 pmol/liter in controls) but increased with decreasing Corli score (P = 0.014) and along the scale of anorexia/hunger (P = 0.0001), which were both related to the 3-d dietary record (P = 0.009 and P 500 pmol/liter) was significantly associated with a low calorie intake [odds ratio (OR), 3.03 for any 100-calorie reduced intake; P = 0.015], a reduced Corli score (OR, 3.09; P = 0.031), and the anorexia score (OR, 3.37; P = 0.009), after adjustment for body mass index. The study confirms the previously observed relationship of fasting ghrelin with food intake in disease-associated malnutrition. In the presence of anorexia, hyperghrelinemia might indicate a compensatory mechanism trying to stimulate food intake, which is nonetheless ineffective in the physiological range.

  11. Hepatitis e and acute liver failure in pregnancy.

    Science.gov (United States)

    Shalimar; Acharya, Subrat K

    2013-09-01

    Hepatitis E virus is a positive strand RNA virus with three open reading frames which is transmitted predominantly through the fecal contamination of water and food. It is the most common cause of acute liver failure in endemic areas. Pregnant women especially from the Indian subcontinent and Africa are at increased risk of contracting acute HEV infection as well as developing severe complications including ALF. Transmission of HEV occurs from mother to unborn child. Both maternal and fetal complications may occur, including abortion, fetal demise, preterm labor and maternal or neonatal death. The precise reasons for increased susceptibility to HEV infection during pregnancy and associated severe disease are still an enigma. Management is supportive and termination of pregnancy is not recommended as a general rule. Prevention of infection is of vital importance, as availability of clean drinking water can reduce the burden of this disease in the community. There is a need for future research to focus on prevention of ALF in pregnancy and to study the disease pathogenesis, which is not explicitly understood at present. The availability of a vaccine may alter the natural course of the disease in this select population which is at risk.

  12. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-04-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content.

  13. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-01-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5–2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content. PMID:27043622

  14. Propylthiouracil-induced liver failure and artificial liver support systems: a case report and review of the literature

    Science.gov (United States)

    Wu, Dong-Bo; Chen, En-Qiang; Bai, Lang; Tang, Hong

    2017-01-01

    Background Antithyroid drugs carry a potential risk of hepatotoxicity. Propylthiouracil (PTU) is commonly prescribed for patients with hyperthyroidism. PTU, however, can induce liver injury, ranging from mild asymptomatic elevation of aminotransferases to acute liver failure (ALF). Case presentation This case reports on a 16-year-old Chinese girl with hyperthyroidism, who was admitted to our hospital for jaundice, nausea, and fatigue associated with severe hyperbilirubinemia and coagulopathy. She had been prescribed PTU 5 months earlier. There was no history of hypersensitivity to drugs, viral liver diseases, blood transfusion, or surgery. On the basis of her symptoms and the clinical data, she was diagnosed with PTU-induced ALF. Due to the limited number of available donor organs for liver transplantation, she was started on treatment with artificial liver support system (ALSS). After four sessions of ALSS, her clinical signs and symptoms were found to be markedly improved, and she was discharged 25 days after admission. Four months later, her liver function normalized. Conclusion Although PTU-induced liver failure is rare in clinical practice, liver function should be appropriately monitored during treatment with PTU. PTU-induced ALF in this patient was successfully managed with an ALSS, suggesting that the latter may be an alternative to liver transplantation. PMID:28138249

  15. Adult-to-adult living donor liver transplantation for acute liver failure in China

    Institute of Scientific and Technical Information of China (English)

    Ding Yuan; Fei Liu; Yong-Gang Wei; Bo Li; Lv-Nan Yan; Tian-Fu Wen; Ji-Chun Zhao

    2012-01-01

    AIM:To investigate the long-term outcome of recipients and donors of adult-to-adult living-donor liver transplantation (AALDLT) for acute liver failure (ALF).METHODS:Between January 2005 and March 2010,170 living donor liver transplantations were performed at West China Hospital of Sichuan University.All living liver donor was voluntary and provided informed consent.Twenty ALF patients underwent AALDLT for rapid deterioration of liver function.ALF was defined based on the criteria of the American Association for the Study of Liver Diseases,including evidence of coagulation abnormality [international normalized ratio (INR) ≥ 1.5] and degree of mental alteration without pre-existing cirrhosis and with an illness of < 26 wk duration.We reviewed the clinical indications,operative procedure and prognosis of AALDTL performed on patients with ALF and corresponding living donors.The potential factors of recipient with ALF and corresponding donor outcome were respectively investigated using multivariate analysis.Survival rates after operation were analyzed using the Kaplan-Meier method.Receiver operator characteristic (ROC) curve analysis was undertaken to identify the threshold of potential risk factors.RESULTS:The causes of ALF were hepatitis B (n =18),drug-induced (n =1) and indeterminate (n =1).The score of the model for end-stage liver disease was 37.1 ± 8.6,and the waiting duration of recipients was 5 ± 4 d.The graft types included right lobe (n=17) and dual graft (n =3).The mean graft weight was 623.3 ± 111.3 g,which corresponded to graft-to-recipient weight ratio of 0.95% ± 0.14%.The segment Ⅴor Ⅷ hepatic vein was reconstructed in 11 right-lobe grafts.The 1-year and 3-year recipient's survival and graft survival rates were 65% (13 of 20).Postoperative results of total bilirubin,INR and creatinine showed obvious improvements in the survived patients.However,the creatinine level of the deaths was increased postoperatively and became more aggravated

  16. Acute liver failure after recommended doses of acetaminophen in patients with myopathies

    NARCIS (Netherlands)

    I. Ceelie (Ilse); L.P. James (Laura); V.M.G.J. Gijsen (Violette); R.A.A. Mathôt (Ron); S. Ito (Shinya); C.D. Tesselaar (Coranne); D. Tibboel (Dick); G. Koren (Gideon); S.N. de Wildt (Saskia)

    2011-01-01

    textabstractObjective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute

  17. Changes in cerebral oxidative metabolism in patients with acute liver failure

    DEFF Research Database (Denmark)

    Bjerring, P N; Larsen, F S

    2013-01-01

    acid cycle, induces substrate depletion through marked glutamate utilization for glutamine synthesis and leads to mitochondrial dysfunction. In patients with acute liver failure cerebral microdialysis studies show a linear correlation between the lactate to pyruvate ratio and the glutamine...

  18. Acute liver failure after recommended doses of acetaminophen in patients with myopathies

    NARCIS (Netherlands)

    I. Ceelie (Ilse); L.P. James (Laura); V.M.G.J. Gijsen (Violette); R.A.A. Mathot (Ron); S. Ito (Shinya); C.D. Tesselaar (Coranne); D. Tibboel (Dick); G. Koren (Gideon); S.N. de Wildt (Saskia)

    2011-01-01

    textabstractObjective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute

  19. Change of liver echogenicity in chronic renal failure: Correlation with serologic test and pathologic findings

    Energy Technology Data Exchange (ETDEWEB)

    Eun, Hyo Won; Cho, Kyoung Sik; Kim, Jeong Kon [Asan Medical Center, Ulsan University College of Medicine, Seoul (Korea, Republic of); Kim, Jung Hoon [Soonchunhyang University School of Medicine, Seoul (Korea, Republic of)

    2002-09-15

    To correlate serologic test and pathologic findings with change of hepatic parenchymal echogenicity on ultrasound (US) in patients with chronic renal failure. From January 1995 to April 2000, among eight hundred eighty four patients with kidney transplantation due to chronic renal failure, sixty seven patients who underwent US-guided liver biopsy were selected. Change of liver echogenicity on US was analyzed, and this change was compared with serologic test and pathologic findings. Among sixty seven patients, pathologic findings of thirty four patients with the normal liver echogenicity on US revealed normal in 15 patients (44%), viral hepatitis in 18 (53%), and liver cirrhosis in one patient (3%). Meanwhile, twenty seven patients with chronic liver disease on US were pathologically confirmed as normal in 13 patients (48%), viral hepatitis in 11 (40%), liver cirrhosis in four patients (11%); six patients with cirrhotic change on US, liver cirrhosis in four patients (67%) and viral hepatitis on two patients (33%). Serologic test of thirty four patients with the normal liver echogenicity on US showed positive HBs Ag in 17 patients (50%), positive anti-HCV Ab in 11 (32%), positive in both HBs Ag and anti-HCV Ab in one (3%), and normal result in five patients (15%). In patients with chronic renal failure, it is nor enough to determine the presence of liver disease only based on change of echogenicity on US. A careful correlation with serologic test and, if needed, pathologic confirmation are recommended for the accurate preoperative evaluation of the liver.

  20. Acute Liver Failure Due to Budd-Chiari Syndrome in the Setting of Cardiac Synovial Sarcoma

    OpenAIRE

    Stine, Jonathan G.; Newton, Kelly; Vinayak, Ajeet G

    2015-01-01

    Primary malignant tumors of the heart, specifically cardiac sarcomas, are rare and mainly diagnosed at autopsy. Acute Budd-Chiari syndrome is a recognized cause of acute liver failure and has been associated with several rare cardiac tumors: atrial myxoma, caval rhabdomyosarcoma, and primary cardiac adenocarcinoma. We present the first case of a fatal, highly differentiated cardiac synovial sarcoma that presented as acute liver failure from Budd-Chiari syndrome.

  1. Acute liver failure | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available nvestigation E.1.2Version 14.1 E.1.2Level LLT E.1.2Classification code 10049844 E.1.2Term Acute liver failur...n(s) being investigated Acute liver failure MedDRA Classification E.1.2 Medical condition or disease under i... General Information on the Trial E.1 Medical condition or disease under investigation E.1.1Medical conditio

  2. Association between Plasma Fibrinogen Levels and Mortality in Acute-on-Chronic Hepatitis B Liver Failure

    OpenAIRE

    Zhexin Shao; Ying Zhao; Limin Feng; Guofang Feng; Juanwen Zhang; Jie Zhang

    2015-01-01

    Acute-on-chronic liver failure (AoCLF) is the most common type of liver failure and is associated with high mortality. Fibrinogen is critical in maintaining primary and secondary hemostasis. Therefore, we prospectively analyzed the association between fibrinogen and outcomes in AoCLF patients. Plasma fibrinogen was measured in 169 AoCLF, 173 chronic hepatitis B (CHB), and 171 healthy patients using a coagulation method. The predictive ability of fibrinogen for 3-month mortality in AoCLF patie...

  3. Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats.

    Science.gov (United States)

    Pradhan, Shrabani; Mandal, Shreya; Roy, Suchismita; Mandal, Arpita; Das, Koushik; Nandi, Dilip K

    2013-04-01

    Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control - receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.

  4. TRANSPLANTATION OF CRYOPRESERVED FETAL LIVER CELLS SEEDED INTO MACROPOROUS ALGINATE-GELATIN SCAFFOLDS IN RATS WITH LIVER FAILURE

    Directory of Open Access Journals (Sweden)

    D. V. Grizay

    2015-01-01

    Full Text Available Aim. To study the therapeutic potential of cryopreserved fetal liver cells seeded into macroporous alginategelatin scaffolds after implantation to omentum of rats with hepatic failure.Materials and methods.Hepatic failure was simulated by administration of 2-acetyl aminofl uorene followed partial hepatectomy. Macroporous alginate-gelatin scaffolds, seeded with allogenic cryopreserved fetal liver cells (FLCs were implanted into rat omentum. To prevent from colonization of host cells scaffolds were coated with alginate gel shell. Serum transaminase activity, levels of albumin and bilirubin as markers of hepatic function were determined during 4 weeks after failure model formation and scaffold implantation. Morphology of liver and scaffolds after implantation were examined histologically. Results. Macroporous alginate-gelatin scaffolds after implantation to healthy rats were colonized by host cells. Additional formation of alginate gel shell around scaffolds prevented the colonization. Implantation of macroporous scaffolds seeded with cryopreserved rat FLCs and additionally coated with alginate gel shell into omentum of rats with hepatic failure resulted in signifi cant improvement of hepatospecifi c parameters of the blood serum and positive changes of liver morphology. The presence of cells with their extracellular matrix within the scaffolds was confi rmed after 4 weeks post implantation.Conclusion. The data above indicate that macroporous alginate-gelatin scaffolds coated with alginate gel shell are promising cell carriers for the development of bioengineered liver equivalents.

  5. Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure.

    Science.gov (United States)

    McKenzie, Rebecca B; Berquist, William E; Nadeau, Kari C; Louie, Christine Y; Chen, Sharon F; Sibley, Richard K; Glader, Bertil E; Wong, Wendy B; Hofmann, Lawrence V; Esquivel, Carlos O; Cox, Kenneth L

    2014-08-01

    In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

  6. Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

    Science.gov (United States)

    Engelmann, G; Meyburg, J; Shahbek, N; Al-Ali, M; Hairetis, M H; Baker, A J; Rodenburg, R J T; Wenning, D; Flechtenmacher, C; Ellard, S; Smeitink, J A; Hoffmann, G F; Buchanan, C R

    2008-08-01

    A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2alpha kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott-Rallison syndrome (WRS). This patient's course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.

  7. Reversible retinal edema in an infant with neonatal hemochromatosis and liver failure.

    Science.gov (United States)

    Maldonado, Ramiro S; Freedman, Sharon F; Cotten, C Michael; Ferranti, Jeffrey M; Toth, Cynthia A

    2011-02-01

    We present a case of bilateral severe retinal edema with subretinal fluid in an infant diagnosed with neonatal hemochromatosis and liver failure. A macular cherry-red spot in each eye mimicked the clinical appearance of many metabolic storage diseases. Both the clinical retinal appearance and the anatomic abnormalities observed on spectral domain optical coherence tomography resolved after successful liver transplant.

  8. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests

    DEFF Research Database (Denmark)

    Korman, J.D.; Volenberg, I.; Balko, J.

    2008-01-01

    Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF ...

  9. Hepatoprotective effects of Paeonia anomala against acetaminophen-induced cell damage through activation of anti-oxidant system

    Directory of Open Access Journals (Sweden)

    O Sarangerel

    2014-10-01

    Full Text Available Overdose of the analgesic and anti-pyretic acetaminophen causes a potentially fatal hepatic necrosis due to a high toxicity and depletion of cellular defense mechanisms. In the present work, the potential hepatoprotective effect of the fruit extract of Paeonia anomala against acetaminophen induced cell damages was evaluated in cultured HepG2 cells and compared to the root extract. The fruit extract showed a potent protection against acetaminophen induced cell death, while the root extract showed a weak protection. Particularly, the pre-treatment of lower doses of the fruit extract, 10 μg/ mL and 20 μg/mL, significantly enhanced cell viability. The level of total glutathione in HepG2 cells treated with the fruit extract prior to the treatment of 40 mM acetaminophen was enhanced, however, the root extract failed for this activity. In addition, activities of quinone reductase, glutathione peroxidase and glutathione reductase were increased and protein levels of glutathione peroxidase 1 and superoxide dismutase 1 were enhanced in the cells treated with 10-20 μg/mL of the fruit extract. Furthermore, the protein level of Nrf2, a crucial regulator for detoxifying and antioxidant systems, was increased by the fruit extract treatment. These results suggest that the fruit extract of P. anomala exerts protective effects against acetaminophen-induced toxicity through activation of key antioxidant systems.DOI: http://dx.doi.org/10.5564/mjc.v14i0.190 Mongolian Journal of Chemistry 14 (40, 2013, p.5-11

  10. Cardiac Failure after Liver Transplantation Requiring a Biventricular Assist Device

    Directory of Open Access Journals (Sweden)

    Rita Jermyn

    2014-01-01

    Full Text Available Increased hepatic iron load in extrahepatic organs of cirrhotic patients with and without hereditary hemochromatosis portends a poorer long term prognosis after liver transplant. Hepatic as well as nonhepatic iron overload is associated with increased infectious and postoperative complications, including cardiac dysfunction. In this case report, we describe a cirrhotic patient with alpha 1 antitrypsin deficiency and nonhereditary hemochromatosis (non-HFE that developed cardiogenic shock requiring mechanical circulatory support for twenty days after liver transplant. Upon further investigation, she was found to have significant iron deposition in both the liver and heart biopsies. Her heart regained complete and sustained recovery following ten days of mechanical biventricular support. This case highlights the importance of preoperatively recognizing extrahepatic iron deposition in patients referred for liver transplantation irrespective of etiology of liver disease as this may prevent postoperative complications.

  11. The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Eefsen, Martin; Hansen, Bent Adel

    2008-01-01

    Acute liver failure (ALF) is a condition with an unfavourable prognosis. Multiorgan failure and circulatory collapse are frequent causes of death, but cerebral edema and intracranial hypertension (ICH) are also common complications with a high risk of fatal outcome. The underlying pathogenesis has...

  12. [Hepatic amyloidosis as a rare differential diagnosis of progressive liver failure].

    Science.gov (United States)

    Bettinger, Dominik; Lutz, Lisa; Schultheiß, Michael; Werner, Martin; Thimme, Robert; Neumann-Haefelin, Christoph

    2016-09-01

    Primary systemic amyloidosis is a rare disorder resulting in extracellular deposition of insoluble fibrils in different organs. Liver involvement has been reported. Since hepatic amyloidosis often presents clinically asymptomatic without specific laboratory or imaging hallmarks, diagnosis is challenging. However, cases of progressive hepatic failure due to liver amyloidosis have been reported. A 63 year old man presented with newly diagnosed ascites to our department. The patient reported occasional alcohol consumption. Viral hepatitis, genetic-metabolic causes as well as hepatic vascular disorders were excluded and ultrasound did not show any signs of liver cirrhosis or intraabdominal malignancy. Initially, alcoholic hepatitis was suspected. Due to the rapid deterioration of liver function, however, transjugular liver biopsy was performed showing light chain amyloidosis of kappa isotype. As diagnosis of hepatic amyloidosis is challenging, early liver biopsy is mandatory in patients with unexplained acute or chronic liver disease to exclude rare diseases with high mortality.

  13. Allocation of patients with liver cirrhosis and organ failure to intensive care

    DEFF Research Database (Denmark)

    Prier Lindvig, Katrine; Søgaard Teisner, Ane; Kjeldsen, Jens

    2015-01-01

    AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit (ICU), and developed a decision tool for clinical practice. METHODS: A systematic review of the literature was performed in PubMed, MEDLINE and EMBASE databases. The search includes studies on hospitalized...... patients with cirrhosis and organ failure, or acute on chronic liver failure and/or intensive care therapy. RESULTS: The initial search identified 660 potentially relevant articles. Ultimately, five articles were selected; two cohort studies and three reviews were found eligible. The literature...... on current available data we developed an algorithm, to determine if a patient is candidate to intensive care if needed, based on three scoring systems: premorbid Child-Pugh Score, Model of End stage Liver Disease score and the liver specific Sequential Organ Failure Assessment score. CONCLUSION...

  14. Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Yumin Xu

    Full Text Available BACKGROUND: Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF. METHODOLOGY: Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. PRINCIPAL FINDINGS: Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats. CONCLUSIONS: sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  15. Artificial and bioartificial liver support: A review of perfusion treatment for hepatic failure patients

    Institute of Scientific and Technical Information of China (English)

    Katsutoshi Naruse; Wei Tang; Masatoshi Makuuchi

    2007-01-01

    Liver transplantation and blood purification therapy, including plasmapheresis, hemodiafiltration, and bioartificial liver support, are the available treatments for patients with severe hepatic failure. Bioartificial liver support, in which living liver tissue is used to support hepatic function, has been anticipated as an effective treatment for hepatic failure. The two mainstream systems developed for bioartificial liver support are extracorporeal whole liver perfusion (ECLP) and bioreactor systems. Comparing various types of bioartificial liver in view of function, safety, and operability, we concluded that the best efficacy can be provided by the ECLP system. Moreover, in our subsequent experiments comparing ECLP and apheresis therapy, ECLP offers more ammonia metabolism than HD and HF. In addition, ECLP can compensate amino acid imbalance and can secret bile. A controversial point with ECLP is the procedure is labor intensive, resulting in high costs. However, ECLP has the potential to reduce elevated serum ammonia levels of hepatic coma patients in a short duration. When these problems are solved, bioartificial liver support, especially ECLP, can be adopted as an option in ordinary clinical therapy to treat patients with hepatic failure.

  16. TREATMENT OF CANINE ACUTE LIVER FAILURE WITH MODIFIED EXTRACORPOREAL PIGLIVER PERFUSION

    Institute of Scientific and Technical Information of China (English)

    王博; 吕毅; 刘昌; 仵正; 潘承恩

    2003-01-01

    Objective To study the theraputic effect of extracorporeal liver perfusion on the treatment of acute liver failure. Methods Mongrel dogs weighing 12-14*!kg were selected. Hepatic failure was induced by an end-to-side portacaval shunt. The common hepatic and gastroduodenal arteries were occluded for 2 hours. To the control group (n=7), the dogs received standard medical therapy . To the treating group (n=10), the dogs received extracorporeal kidney and liver perfusion at the onset of the occlusion of the hepatic artery. During the liver support, the animals were frequently monitored regarding their clinical state, liver function, biochemical and hematological parameters. Results After the occlusion of the liver blood flow, all dogs died within 3-7.5 hours. The average survival time was (5.7±1.2) hours. Serum levels of ALT, AST, LDH and ammonia increased significantly. In the treating group, the dogs died within 7-10.5 hours. The average survival time was 8.6±1.1 hours. There were no significant diferences in serum levels of ALT, AST, LDH between the two groups(P>0.05). There were dramatic diferences in blood Ammonia level, PT, FIB between the two groups(P<0.05). The survival time was longer in treating group. The animals' blood pressure were more stable in the treating group than that in the control group. Conclusion The modified xenogenic liver perfusion can provide necessary hepatic function for the acute liver failure dogs.

  17. Cost-utility of molecular adsorbent recirculating system treatment in acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Taru; Kantola; Suvi; Mklin; Anna-Maria; Koivusalo; Pirjo; Rsnen; Anne; Rissanen; Risto; Roine; Harri; Sintonen; Krister; Hckerstedt; Helena; Isoniemi

    2010-01-01

    AIM:To determine the short-term cost-utility of mo-lecular adsorbent recirculating system(MARS) treatment in acute liver failure(ALF).METHODS:A controlled retrospective study was conducted with 90 ALF patients treated with MARS from 2001 to 2005.Comparisons were made with a historical control group of 17 ALF patients treated from 2000 to 2001 in the same intensive care unit(ICU) specializing in liver diseases.The 3-year outcomes and number of liver transplantations were recorded.All direct liver disease-rel...

  18. Liver regeneration signature in hepatitis B virus (HBV-associated acute liver failure identified by gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Oriel Nissim

    Full Text Available INTRODUCTION: The liver has inherent regenerative capacity via mitotic division of mature hepatocytes or, when the hepatic loss is massive or hepatocyte proliferation is impaired, through activation of hepatic stem/progenitor cells (HSPC. The dramatic clinical course of acute liver failure (ALF has posed major limitations to investigating the molecular mechanisms of liver regeneration and the role of HSPC in this setting. We investigated the molecular mechanisms of liver regeneration in 4 patients who underwent liver transplantation for hepatitis B virus (HBV-associated ALF. METHODS AND FINDINGS: Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two clusters of ALF that segregated according to histopathological severity massive hepatic necrosis (MHN; 2 patients and submassive hepatic necrosis (SHN; 2 patients. We found that ALF is characterized by a strong HSPC gene signature, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of stem cell genes (EpCAM, CK19, CK7, whereas the most up-regulated genes in SHN were related to cellular growth and proliferation. The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound-healing process. CONCLUSION: Our data provide evidence for a distinct gene signature in HBV-associated ALF whose intensity is directly correlated with the histopathological severity. HSPC activation and fibrogenesis positively correlated with the extent of liver necrosis. Moreover, we detected a tumorigenesis gene signature

  19. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein

    Directory of Open Access Journals (Sweden)

    Kopylchuk G.P.

    2015-09-01

    Full Text Available Background. Acetaminophen is known as inducer of acute hepatotoxicity. Extrahepatic manifestations of acetaminophen toxicity are poorly understood in particular its nephrotoxicity. Objective. The purpose of this study was the morphological characteristic of rat kidneys under the conditions of acetaminophen-induced nephrotoxicity on the background of alimentary deprivation of protein. Methods. Аfter administration of the toxic dose of acetaminophen and maintenance of rats on a different regimen of protein nutrition their kidneys were sectioned and stained with hematoxylin and eosin according to a standard technique. Results. It was estimated, that in rats maintained during long period of time under the conditions of alimentary deprivation of protein, and in rats injected with toxic dose of acetaminophen morphological changes of kidney were not observed. Administration of acetaminophen on the background of previous protein deficiency causes the pathological changes of kidney morphology with papillary necrosis as a key sign. Conclusion. Alimentary deprivation of protein in case of acetaminophen injection is the critical factor for the impairment of structural integrity of kidney tissue with its subsequent dysfunction. Citation: Kopylchuk GP, Voloshchuk ON, Buchkovskaia IM, Davydenko IS. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein]. Morphologia. 2015;9(3:28-30. Russian.

  20. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury.

    Science.gov (United States)

    Naguib, Yahya M; Azmy, Rania M; Samaka, Rehab M; Salem, Mohamed F

    2014-12-15

    Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects. Ninety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal. APAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues. We report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative

  1. Arterial steroid injection therapy can inhibit the progression of severe acute hepatic failure toward fulminant liver failure

    Institute of Scientific and Technical Information of China (English)

    Kazuhiro Kotoh; Tsuyoshi Tajima; Yoshiki Asayama; Kousei Ishigami; Masakazu Hirakawa; Munechika Enjoji; Makoto Nakamuta; Tsuyoshi Yoshimoto; Motoyuki Kohjima; Shusuke Morizono; Shinsaku Yamashita; Yuki Horikawa; Kengo Yoshimitsu

    2006-01-01

    AIM: To utilize transcatheter arterial steroid injection therapy (TASIT) via the hepatic artery to reduce hepatic macrophage activity in patients with severe acute hepatic failure.METHODS: Thirty-four patients with severe acute hepatic failure were admitted to our hospital between June 2002 to June 2006 providing for the possibility of liver transplantation (LT). Seventeen patients were treated using traditional liver supportive procedures, and the other 17 patients additionally underwent TASIT with 1000 mg methylprednisolone per day for 3 continuous days.RESULTS: Of the 17 patients who received TASIT, 13 were cured without any complications, 2 died, and 2 underwent LT. Of the 17 patients who did not receive TASIT, 4 were self-limiting, 7 died, and 6 underwent LT.Univariate logistic analysis revealed that ascites, serum albumin, prothrombin time, platelet count, and TASIT were significant variables for predicating the prognosis.Multivariate logistic regression analysis using stepwise variable selection showed that prothrombin time, platelet count, and TASIT were independent predictive factors.CONCLUSION: TASIT might effectively prevent the progression of severe acute hepatic failure to a fatal stage of fulminant liver failure.

  2. Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

    Science.gov (United States)

    Thiel, Karolin; Klingert, Wilfried; Klingert, Kathrin; Morgalla, Matthias H; Schuhmann, Martin U; Leckie, Pamela; Sharifi, Yalda; Davies, Nathan A; Jalan, Rajiv; Peter, Andreas; Grasshoff, Christian; Königsrainer, Alfred; Schenk, Martin; Thiel, Christian

    2017-01-01

    AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose. METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy. RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P 0.01). CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model. PMID:28321158

  3. Epidemiological and clinical features of hepatitis B virus related liver failure in China

    Institute of Scientific and Technical Information of China (English)

    Chen Liu; Yu-Ming Wang; Ke Fan

    2011-01-01

    AIM: To examine the epidemiologic and clinical characteristics of hepatitis B virus (HBV) related liver failure in patients in China. METHODS: This study was conducted with a retrospective design to examine 1066 patients with HBVrelated liver failure in the southwest of China. RESULTS: There were more male than female patients. Young and middle-aged people comprised most of the patients. Farmers and laborers comprised the largest proportion (63.09%). Han Chinese accounted for 98.12%, while minority ethnic groups only accounted for 0.88% of patients. A total of 43.47% patients had a family history of HBV-related liver failure and 56.66% patients had a history of drinking alcohol. A total of 42.59% patients with HBV-related liver failure had definite causes. With regard to the clinical manifestation of HBV-related liver failure, the symptoms were: hypodynamia, anorexia and abdominal distension. Total bilirubin (TBIL) and alanine aminotransferase (ALT) levels were altered in 46.23% of patients with evident damage of the liver. Univariate logistic regression analysis showed that the patients' prognoses were correlated with ALT, aspartate aminotransferase, albumin, TBIL, prothrombin activity (PTA), and alpha-fetoprotein levels, and drinking alcohol, ascites, hepatorenal syndrome, infection and ≥ 2 complications. Multifactor logistic regression analysis showed that the activity of thrombinogen and the number of complications were related to the prognosis. CONCLUSION: Alcohol influences the patients' prognosis and condition. PTA and complications are independent factors that can be used for estimating the prognosis of HBV-related liver failure.

  4. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

    Science.gov (United States)

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  5. The use Prometheus FPSA system in the treatment of acute liver failure: preliminary results.

    Science.gov (United States)

    Skwarek, A; Grodzicki, M; Nyckowski, P; Kotulski, M; Zieniewicz, K; Michalowicz, B; Patkowski, W; Grzelak, I; Paczkowska, A; Giercuszkiewicz, D; Sańko-Resmer, J; Paczek, L; Krawczyk, M

    2006-01-01

    The preliminary outcomes of patients with acute liver failure treated with the Prometheus Fractionated Plasma Separation and Absorption (FPSA) system are presented herein. The procedures were performed in 13 patients (4, intoxication by Amanita phalloides; 4, unknown reason; 3, acetaminophen intoxication; 1, Wilson disease, and 1, liver insufficiency after hemihepatectomy owing to metastases of colon adenocarcinoma). The patients were qualified for the procedure according to the King's College Hospital criteria. The patients' general status was assessed on basic of GCS, UNOS, and the 4-grade encephalopathy classifications. The procedures were performed with the Prometheus 4008H Fresenius Medical Care unit. The 29 procedures were of mean duration 6.5 hours. There were statistically significant reductions in total bilirubin, ammonia, and aminotransferase levels. In addition, the procedures corrected water, mineral, and carbohydrate disorders. One patient did not require liver transplantation. Seven patients received liver transplants: three patients with positive outcomes; two died due to septicemia within 30 days perioperatively, one died at 6 months after OLT owing to respiratory failure; and one, owing to hemorrhagic diathesis. Four patients did not receive a liver transplant because of lack of a organ, no consent for the surgery, or neoplastic disease with metastases. The Prometheus FPSA-System was an effective detoxication method for patients with acute liver failure. The system was useful as a symptomatic treatment before liver transplantation allowing a longer wait for a graft.

  6. Low levels of blood lipids are associated with etiology and lethal outcome in acute liver failure.

    Directory of Open Access Journals (Sweden)

    Paul Manka

    Full Text Available Emerging data links different aspects of lipid metabolism to liver regeneration. In patients with acute liver failure (ALF, low levels of lipids may correlate with disease severity. Thus, we determined whether there is an etiology-specific link between lipid levels in patients suffering from ALF and aimed to investigate an effect of lipid levels on the prognosis of ALF.In this retrospective single center study, we reviewed 89 consecutive ALF patients, who met the criteria of the "Acute Liver Failure Study Group". Patient characteristics, clinical data and laboratory parameters were individually analyzed at admission and correlated with the patients' outcome after a four week follow up. Possible endpoints were either discharge, or death or liver transplantation.High-density lipoprotein (HDL, cholesterol and triglyceride levels were significantly lower in patients who died or required a liver transplant. HDL levels were significantly higher in patients with ALF caused by acetaminophen intoxication, compared to fulminant HBV infection or drug induced liver injury. HDL levels correlated with hepatic injury by ALT levels, and Albumin, and inversely correlated with the MELD score, INR, and bilirubin.In our cohort of patients with ALF, we could show that HDL and cholesterol are suppressed. In addition novel etiology specific patterns between acteminophen and non-acteminophen induced liver failure were detected for serum lipid components. Further studies are needed to address the role of cholesterol and lipid metabolism and the according pathways in different etiologies of ALF.

  7. Effect of extracorporeal bioartificial liver support system on fulminant hepatic failure rabbits

    Institute of Scientific and Technical Information of China (English)

    Ying Jie Wang; Meng Dong Li; Yu Ming Wang; Guo Zheng Chen; Guo Dong Lu; Zao Xia Tan

    2000-01-01

    AIM To evaluate the possibility of using cultured human hepatocytes as a bridge between bioartificial liver and liver transplantation. METHODS In this experiment, the efficacy of extracorporeal bioartificial liver support system (EBLSS) consisting of spheriodal human liver cells and cultured hepatocytes supernatant was assessed in vivo using galactosamine induced rabbit model of fulminant hepatic failure. RiESULTS There was no difference of survival between the two groups of rabbits, but in the supported rabbits serum alanine aminotransferase, total bilirubin and creatinine were significantly lower and hepatocyte necrosis was markedly milder than those in control animals. In addition, a good viability of human liver cells was noted after the experiment. CONCLUSION EBLSS plays a biologic role in maintaining and compensating the function of the liver.

  8. Comparison between bioartificial and artificial liver for the treatment of acute liver failure in pigs

    Institute of Scientific and Technical Information of China (English)

    Yasushi Kawazoe; Susumu Eguchi; Nozomu Sugiyama; Yukio Kamohara; Hikaru Fujioka; Takashi Kanematsu

    2006-01-01

    AIM: To characterize and evaluate the therapeutic efficacy of bioartificial liver (BAL) as compared to that of continuous hemodiafiltration (CHDF) with plasma exchange (PE), which is the current standard therapy for fulminant hepatic failure (FHF) in Japan.METHODS: Pigs with hepatic devascularization were divided into three groups: (1) a non-treatment group (NT; n = 4); (2) a BAL treatment group (BAL; n = 4),(3) a PE + CHDF treatment group using 1.5 L of normal porcine plasma with CHDF (PE + CHDF, n = 4). Our BAL system consisted of a hollow fiber module with 0.2 μm pores and 1 × 1010 of microcarrier-attached hepatocytes inoculated into the extra-fiber space. Each treatment was initiated 4 h after hepatic devascularization.RESULTS: The pigs in the BAL and the PE + CHDF groups survived longer than those in the NT group. The elimination capacity of blood ammonia by both BAL and PE + CHDF was significantly higher than that in NT.Aromatic amino acids (AAA) were selectively eliminated by BAL, whereas both AAA and branched chain amino acids, which are beneficial for life, were eliminated by PE + CHDF.Electrolytes maintenance and acid-base balance were better in the CPE + CHDF group than that in the BAL group.CONCLUSION: Our results suggest that PE + CHDF eliminate all factors regardless of benefits, whereas BAL selectively metabolizes toxic factors such as AAA.However since PE + CHDF maintain electrolytes and acid-base balance, a combination therapy of BAL plus CPE + CHDF might be more effective for FHF.

  9. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report.

    Science.gov (United States)

    Abkur, Tarig Mohammed; Mohammed, Waleed; Ali, Mohamed; Casserly, Liam

    2014-12-06

    5-oxoproline (pyroglutamic acid), an organic acid intermediate of the gamma-glutamyl cycle, is a rare cause of high anion gap metabolic acidosis. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We believe that reporting all cases of 5-oxoprolinemia will contribute to a better understanding of this disease. Here, we report the case of a patient who developed transient 5-oxoprolinemia following therapeutic acetaminophen use. A 75-year-old Caucasian woman was initially admitted for treatment of an infected hip prosthesis and subsequently developed transient high anion gap metabolic acidosis. Our patient received 40 g of acetaminophen over a 10-day period. After the more common causes of high anion gap metabolic acidosis were excluded, a urinary organic acid screen revealed a markedly increased level of 5-oxoproline. The acidosis resolved completely after discontinuation of the acetaminophen. 5-oxoproline acidosis is an uncommon cause of high anion gap metabolic acidosis; however, it is likely that it is under-diagnosed as awareness of the condition remains low and testing can only be performed at specialized laboratories. The diagnosis should be suspected in cases of anion gap metabolic acidosis, particularly in patients with recent acetaminophen use in combination with sepsis, malnutrition, liver disease, pregnancy or renal failure. This case has particular interest in medicine, especially for the specialties of nephrology and orthopedics. We hope that it will add more information to the literature about this rare condition.

  10. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

  11. Hepatic Copper Accumulation: A Novel Feature in Transient Infantile Liver Failure Due to TRMU Mutations?

    Science.gov (United States)

    Grover, Z; Lewindon, P; Clousten, A; Shaag, A; Elpeleg, O; Coman, D

    2015-01-01

    Defects in the mitochondrial respiratory chain can induce a heterogeneous range of clinical and biochemical manifestations. Hepatic involvement includes acute fulminant hepatic failure, microvesicular steatosis, neonatal non-alloimmune haemochromatosis and cirrhosis. Recently pathogenic mutations in tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) gene (OMIM 610230) have been demonstrated to cause transient infantile liver failure (OMIM 613070). The human TRMU gene encodes a mitochondrial protein, 5-methylaminomethyl-2-thiouridylate methyltransferase, whose molecular function is that of mitochondrial tRNA modification.We report an infant who presented with acute liver failure, in whom we observed hepatic copper intoxication and cirrhosis on liver biopsy. We postulate that the hepatic copper intoxication observed in our patient is most likely a secondary event associated with cholangiopathy. Periportal copper accumulation has been implicated in causing secondary mitochondrial dysfunction; the impact of copper accumulation in patients with TRMU mutations is unclear and warrants long-term clinical follow-up.

  12. Rapid Recovery from Acute Liver Failure Secondary to Pancreatoduodenectomy-Related Non-Alcoholic Steatohepatitis

    Directory of Open Access Journals (Sweden)

    Kazushige Nirei

    2013-01-01

    Full Text Available This report describes a case of liver failure secondary to pancreatoduodenectomy and rapid recovery following treatment. A 68-year-old woman with cancer on the ampulla of Vater underwent surgery for pancreatoduodenectomy. The patient developed liver failure 3 months postsurgically. She was hospitalized after presenting with jaundice, hypoalbuminemia and decreased serum zinc. Computed tomography (CT of the abdomen showed a reduction in CT attenuation values postoperatively. We suspected fatty liver due to impaired absorption caused by pancreatoduodenectomy. We initiated treatment with branched-chain amino acids and a zinc formulation orally. Trace elements were administered intravenously. Two months after treatment, there was a noticeable improvement in CT findings. The patient’s jaundice and hypoalbuminemia prompted a liver biopsy, which led to a diagnosis of non-alcoholic steatohepatitis.

  13. Liver transplantation for acute hepatic failure due to chemotherapy-induced HBV reactivation in lymphoma patients

    Institute of Scientific and Technical Information of China (English)

    Timothée Noterdaeme; Luc Longrée; Christian Bataille; Arnaud Deroover; Anne Lamproye; Jean Delwaide; Yves Beguin; Pierre Honoré; Olivier Detry

    2011-01-01

    Hepatitis B (HBV) reactivation induced by chemotherapy is problem encountered recently in the management of malignant diseases. Chemotherapy-induced HBV reactivation may ultimately lead to terminal acute liver failure. Liver transplantation (LT) currently remains the only definitive treatment option for such cases, but is generally denied to patients suffering from malignancy. Here, the authors describe 2 cases of cancer-free and HBV graft re-infection-free survival after LT performed for terminal liver failure arising from HBV reactivation induced by chemotherapy for advanced stage lymphoma. These 2 cases, and some other reports in the literature, may suggest that patients suffering from hematologic malignancies and terminal liver disease can be considered for LT if the prognosis of their hematologic malignancy is good.

  14. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  15. A case report of congenital umbilical arteriovenous malformation complicated with liver failure after surgical excision

    Science.gov (United States)

    Han, Ji-Won; Kim, Hyun-Young; Jung, Sung-Eun

    2017-01-01

    Abstract Rationale: Few case reports of umbilical arteriovenous malformation (AVM) have been reported. Herein, we report a neonatal case of umbilical AVM who underwent liver failure after surgical excision. Patient concerns: The patient was a girl delivered at a gestational age of 39+5 weeks showing cyanosis and heart murmur. Diagnoses: Cardiac echography, abdominal ultrasonography (USG), and computed tomography revealed suspecting the umbilical AVM. Interventions: On the eighth day after birth, because of the aggravation of heart failure, emergency surgery for excision of umbilical AVM was performed. Outcomes: In postoperative state, worsened laboratory test of liver function and coagulopathy indicated the liver failure. Abdominal USG revealed that the portal vein (PV) flow primarily occurred from the left PV to the inferior vena cava via ductus venosus and coarse hepatic echogenicity. After conservative management, laboratory findings of liver function and the flow direction of the left PV were normal, as demonstrated by abdominal USG within 50th postoperative day. Lessons: Careful preoperative evaluation of an AVM of a large size with significant blood flow should be performed, and the possibility of liver failure after surgery should always be considered. PMID:28178121

  16. Hepatitis A related acute liver failure by consumption of contaminated food.

    Science.gov (United States)

    Chi, Heng; Haagsma, Elizabeth B; Riezebos-Brilman, Annelies; van den Berg, Arie P; Metselaar, Herold J; de Knegt, Robert J

    2014-11-01

    We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the King's College criteria for acute liver failure. Two days after admission, he underwent liver transplantation and recovered. Careful investigation identified imported semi-dried tomatoes as the source of the hepatitis A infection. This patient was part of a foodborne hepatitis A outbreak in the Netherlands in 2010 affecting 13 patients. Virus sequence analysis of our patient's virus showed a strain commonly found in Turkey. Hepatitis A related acute liver failure is rare, but is associated with a poor prognosis. In developed countries, the incidence of hepatitis A is low, but foodborne outbreaks are emerging. Further, we review the literature on recent foodborne hepatitis A outbreaks in developed countries, hepatitis A related acute liver failure, and hepatitis A vaccine. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Optimizing management in autoimmune hepatitis with liver failure at initial presentation

    Institute of Scientific and Technical Information of China (English)

    Jonathan R Potts; Sumita Verma

    2011-01-01

    Autoimmune hepatitis (AIH) is a disease of unknown etiology, its hallmark being ongoing hepatic inflamma-tion. By its very nature, it is a chronic condition, al-though increasingly, we are becoming aware of patients with acute presentations, some of whom may have liver failure. There are very limited published data on patients with AIH with liver failure at initial diagnosis, which consist mostly of small retrospective studies. As a consequence, the clinical features and optimal management of this cohort remain poorly defined. A subset of patients with AIH who present with liver failure do respond to corticosteroids, but for the vast majority, an urgent liver transplantation may offer the only hope of long-term survival. At present, there is uncertainty on how best to stratify such a cohort into responders and non-responders to corticosteroids as soon as possible after hospitalization, thus optimizing their management. This editorial attempts to answer some of the unre-solved issues relating to management of patients with AIH with liver failure at initial presentation. However, it must be emphasized that, at present, this editorial is based mostly on small retrospective studies, and it is an understatement that multicenter prospective studies are urgently needed to address this important clinical issue.

  18. HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

    Full Text Available Acute liver failure (ALF is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT. BT triggers/induces systemic inflammatory responses syndrome (SIRS, which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

  19. Fatal subacute liver failure after repeated administration of sevoflurane anaesthesia.

    Science.gov (United States)

    Zizek, David; Ribnikar, Marija; Zizek, Bogomir; Ferlan-Marolt, Vera

    2010-01-01

    Sevoflurane is a widely used halogenated inhalation anaesthetic. In comparison with other similar anaesthetics, it is not metabolized to potentially hepatotoxic trifluoroacetylated proteins. In this case report, we present a 66-year-old woman with breast carcinoma, who underwent sevoflurane general anaesthesia twice in 25 days. Soon after the second elective surgical procedure, jaundice and marked elevations in serum transaminases developed. The patient died 66 days thereafter. Autopsy results denied evidence of major cardiovascular abnormality, and histological examination confirmed massive liver cell necrosis with no feature of chronic liver injury. Sevoflurane anaesthesia was imputed as the cause after exclusion of other possible aetiological agents. Besides, coexistent malignant tumours found in the patient could have modulated the immunological response to the applied anaesthetic followed by fatal consequences.

  20. Emergency adult living donor right lobe liver transplantation for fulminant hepatic failure

    Institute of Scientific and Technical Information of China (English)

    ZHANG Feng; LU Sheng; PU Liyong; LU Ling; WANG Xuehao; LI Xiangcheng; KONG Lianbao; SUN Beicheng; LI Guoqiang; QIAN Xiaofen; CHEN Feng; WANG Ke

    2007-01-01

    Fulminant hepatitis is fatal in most cases and timely liver transplantation is the only effective treatment.This study evaluates the survival outcomes of patients who underwent living-donor liver transplantation (LDLT)using right lobe liver grafts for fulminant liver failure due to hepatitis B infection.Nine cases of adult right lobe LDLT were performed in our department from September 2002 to August 2005 and the clinical and following-up data were reviewed.According to the pre-transplant Child-Pugh-Turcotte classification,the nine patients were classified as grade C.The model for end-stage liver disease (MELD) score of these patients ranged from 16 to 42.The principal complications before transplantation included abnormal renal function,hepatic coma of different degrees and alimentary tract hemorrhage.The main complications after transplantation included pulmonary infection in two cases,acute renal failure in three cases and transplantation-related encephalopathy in one case.No primary failure of vascular or biliary complications occurred.The one-year survival rate was 55.6%.There were no serious complications or deaths in donors.In general,it is extremely difficult to treat fulminant hepatitis by conservative regimen,particularly,in cases with rapid progresslon.Emergency adult living-donor liver transplantation is an effective treatment for fulminant hepatitis patients and is relatively safe for donors.

  1. Downgrading MELD improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure.

    Directory of Open Access Journals (Sweden)

    Qi Ling

    Full Text Available BACKGROUND: High score of model for end-stage liver diseases (MELD before liver transplantation (LT indicates poor prognosis. Artificial liver support system (ALSS has been proved to effectively improve liver and kidney functions, and thus reduce the MELD score. We aim to evaluate whether downgrading MELD score could improve patient survival after LT. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and twenty-six LT candidates with acute-on-chronic hepatitis B liver failure and MELD score ≥30 were included in this prospective study. Of the 126 patients, 42 received emergency LT within 72 h (ELT group and the other 84 were given ALSS as salvage treatment. Of the 84 patients, 33 were found to have reduced MELD score (40 years and the interval from last ALSS to LT >48 h were independent negative influence factors of downgrading MELD. CONCLUSIONS/SIGNIFICANCE: Downgrading MELD for liver transplant candidates with MELD score ≥30 was effective in improving patient prognosis. An appropriate ALSS treatment within 48 h prior to LT is potentially beneficial.

  2. Treatment modalities in experimentally induced acute liver failure

    NARCIS (Netherlands)

    P.T. Ernst

    1988-01-01

    textabstractThe findings made in the presented study suggest that one or more still unknown factors inherent in the experimental models currently in use are of critical importance and that only a certain limited type of model of acute hepatic failure is suitable for the evaluation of the effectivene

  3. HFRS with Severe Heart Liver and Renal Failure:a Case Report

    Institute of Scientific and Technical Information of China (English)

    Qing; Zhou; Meng-Hou; Lu; Lei; Fu; De-Ming; Tan

    2012-01-01

    Hemorrhagic fever with renal syndrome(HFRS) is caused by hantavirus infection,which was characterized by abrupt high fever,systemic hemorrhage,hypotension and renal damage.Although multiple system organ damage was not uncommon,but multiple organ system failure were rare.Hereafter we report one case with simultaneous renal,heart and liver failure.In this case,we received some experience and lessons.

  4. Role of monocytes and macrophages in experimental and human acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Lucia; A; Possamai; Charalambos; Gustav; Antoniades; Quentin; M; Anstee; Alberto; Quaglia; Diego; Vergani; Mark; Thursz; Julia; Wendon

    2010-01-01

    Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of AL...

  5. Hepatic failure in a rapidly involuting congenital hemangioma of the liver: failure of embolotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Zenzen, Wendy; Alomari, Ahmad I. [Children' s Hospital Boston, Division of Vascular and Interventional Radiology, Department of Radiology, Boston, MA (United States); Perez-Atayde, Antonio R. [Children' s Hospital Boston and Harvard Medical School, Department of Pathology, Boston, MA (United States); Elisofon, Scott A. [Children' s Hospital Boston and Harvard Medical School, Division of Gastroenterology, Boston, MA (United States); Bae Kim, Heung [Children' s Hospital Boston and Harvard Medical School, Department of Surgery, Boston, MA (United States)

    2009-10-15

    We report the clinical course, imaging findings, and management of a rare case of rapidly involuting congenital hemangioma of the liver in a newborn girl. The baby presented with severe progressive hepatic dysfunction and cardiomegaly. Multimodality imaging demonstrated a large hypervascular solitary hepatic mass with marked transhepatic shunting, consistent with rapidly involuting congenital hemangioma. Because medical therapy failed, transarterial and transvenous embolization was performed with the main intention to improve the hepatic perfusion and function. Unfortunately, despite improvement in the cardiac overload, liver function continued to deteriorate. The baby eventually underwent successful liver transplantation. (orig.)

  6. Chronic Liver Failure after Treatment with Infliximab for Ankylosing Spondylitis in a Patient with Hepatitis B

    Institute of Scientific and Technical Information of China (English)

    2013-01-01

    A 50-year-old man with ankylosing spondylitis was treated successfully with inlfiximab, who was also a HBV carrier for about twenty-ifve years. After injection with inlfiximab for four times, he developed jaundice and HBV DNA was detectable in serum. Serum aminotransferase and total bilirubin levels were higher than normal. Then he was hospitalized and treated with entacavir and Chinese herb medicine. But his liver damage aggravated and was diagnosed as acute on chronic liver failure. Finally, liver transplantation was carried out and he was cured successfully.

  7. Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure

    Science.gov (United States)

    Xiao, Yong-Tao; Cao, Yi; Zhou, Ke-Jun; Lu, Li-Na; Cai, Wei

    2016-01-01

    Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = −0.50, p CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients. PMID:27976737

  8. Methanobactin reverses acute liver failure in a rat model of Wilson disease

    Science.gov (United States)

    Lichtmannegger, Josef; Leitzinger, Christin; Wimmer, Ralf; Schmitt, Sabine; Schulz, Sabine; Eberhagen, Carola; Rieder, Tamara; Janik, Dirk; Neff, Frauke; Straub, Beate K.; Schirmacher, Peter; DiSpirito, Alan A.; Bandow, Nathan; Baral, Bipin S.; Flatley, Andrew; Kremmer, Elisabeth; Denk, Gerald; Reiter, Florian P.; Hohenester, Simon; Eckardt-Schupp, Friedericke; Dencher, Norbert A.; Sauer, Vanessa; Niemietz, Christoph; Schmidt, Hartmut H.J.; Merle, Uta; Gotthardt, Daniel Nils; Kroemer, Guido; Weiss, Karl Heinz

    2016-01-01

    In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration– and European Medicines Agency–approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD. PMID:27322060

  9. Safety and Efficacy of Anidulafungin for Fungal Infection in Patients With Liver Dysfunction or Multiorgan Failure

    Science.gov (United States)

    Auzinger, Georg; Kantecki, Michal; Campling, James; Spurden, Dean; Percival, Fran; Heaton, Nigel

    2017-01-01

    Abstract Background. The objective of this study was to review our clinical experience on the safety and efficacy of anidulafungin, an echinocandin antifungal, in the treatment of invasive fungal infections (IFIs) in patients with moderate to severe abnormal liver function tests or multiorgan failure and IFI, in a large United Kingdom Liver Centre. Methods. The clinical records of the first 50 consecutive patients treated for IFI with anidulafungin between January 7, 2009 and March 2, 2011 were analyzed. Data were collected on demographics, underlying disease, disease characteristics, hematological and biochemical parameters, IFI, concomitant bacterial and viral infections, response to anidulafungin, and anidulafungin-related adverse events. Results. The patients’ median age was 54.3 years (range, 19.6–75.9); 60% were male. Twenty-two (44%) patients were liver transplant recipients. Others had hepatopancreaticobiliary disease (n = 15, 30%) or chronic liver disease (n = 11, 22%). Invasive fungal infection (predominantly Candida spp) was proven in 36 (72%) patients, probable in 14 (28%). Of 46 evaluable patients, 35 (76%) had a favorable anidulafungin treatment outcome. Forty-nine (98%) had abnormal liver function tests (LFTs) pretreatment; 31 (62%) had ≥1 LFT raised to ≥2× baseline during anidulafungin treatment. Conclusions. In this highly specialized group of patients, anidulafungin treatment was efficacious and well tolerated by those with decompensated liver disease, multiorgan failure, and high-risk liver transplant with proven or probable IFI. PMID:28480239

  10. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.

    Science.gov (United States)

    Arai, Tomoya; Koyama, Ryo; Yuasa, Makoto; Kitamura, Daisuke; Mizuta, Ryushin

    2014-01-01

    Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.

  11. A Rare Cause of Neonatal Liver Failure: Neonatal Hemochromatosis

    Directory of Open Access Journals (Sweden)

    Uluca Ü et al.

    2013-09-01

    Full Text Available Neonatal hemochromatosis (NH is a severe rare liver disease in neonatal period associated with ekstrahepatic siderosis. This disease is characterized by hepatocellular insufficiency that presented with jaundice, hypoglycemia, hypoalbuminemia, low fibrinogen levels, thrombocytopenia, anemia, direct and indirect hyperbilirubinemia from the first days of life. Herein we reported a case with Rh incompatibility whose jaundice was noted at the first day of life and referred to our hospital for exchange transfusion, but thereafter diagnosed as NH and reviewed the literature in the view point of the latest developments related to the topic.

  12. Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes.

    Science.gov (United States)

    Kon, Kazuyoshi; Kim, Jae-Sung; Uchiyama, Akira; Jaeschke, Hartmut; Lemasters, John J

    2010-09-01

    Acetaminophen induces the mitochondrial permeability transition (MPT) in hepatocytes. Reactive oxygen species (ROS) trigger the MPT and play an important role in AAP-induced hepatocellular injury. Because iron is a catalyst for ROS formation, our aim was to investigate the role of chelatable iron in MPT-dependent acetaminophen toxicity to mouse hepatocytes. Hepatocytes were isolated from fasted male C3Heb/FeJ mice. Necrotic cell killing was determined by propidium iodide fluorometry. Mitochondrial membrane potential was visualized by confocal microscopy of tetramethylrhodamine methylester. Chelatable ferrous ion was monitored by calcein quenching, and 70 kDa rhodamine-dextran was used to visualize lysosomes. Cell killing after acetaminophen (10mM) was delayed and decreased by more than half after 6 h by 1mM desferal or 1mM starch-desferal. In a cell-free system, ferrous but not ferric iron quenched calcein fluorescence, an effect reversed by dipyridyl, a membrane-permeable iron chelator. In hepatocytes loaded with calcein, intracellular calcein fluorescence decreased progressively beginning about 4 h after acetaminophen. Mitochondria then depolarized after about 6 h. Dipyridyl (20mM) dequenched calcein fluorescence. Desferal and starch-desferal conjugate prevented acetaminophen-induced calcein quenching and mitochondrial depolarization. As calcein fluorescence became quenched, lysosomes disappeared, consistent with release of iron from ruptured lysosomes. In conclusion, an increase of cytosolic chelatable ferrous iron occurs during acetaminophen hepatotoxicity, which triggers the MPT and cell killing. Disrupted lysosomes are the likely source of iron, and chelation of this iron decreases acetaminophen toxicity to hepatocytes.

  13. Interaction between nitric oxide synthase and cyclooxygenase in the development of acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Meltem Kolgazi

    2015-03-01

    Results: AG and KET prevented the increase in liver malondialdehyde levels due to APAP toxicity. Decreased liver glutathione in APAP group was prevented by all treatments except NIM. Stimulated liver myeloperoxidase activity in APAP group was attenuated by all treatments except INDO and NIM. Elevation of liver chemiluminescence, nuclear factor (NF- and #61547;B expression and serum alanine transferase level due to APAP overdose were also suppressed by all treatments. Conclusions: NOS and COX pathways interact in the development of hepatotoxicity due to APAP overdose. [J Exp Integr Med 2015; 5(1.000: 16-22

  14. Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit

    NARCIS (Netherlands)

    C.C.D. van der Rijt (Carin); R.J. de Knegt (Robert); S.W. Schalm (Solko); O.T. Terpstra (Onno); K. Mechelse (Karel)

    1990-01-01

    textabstractThe effect of flumazenil, a benzodiazepine antagonist, on hepatic encephalopathy was studied in rabbits with acute hepatic failure induced by a two-stage liver devascularization procedure. The rabbits were randomized for treatment with 5 mg/kg of flumazenil or the placebo. The drug was a

  15. Pediatric acute liver failure : variations in referral timing are associated with disease subtypes

    NARCIS (Netherlands)

    Sturm, Ekkehard; Lexmond, Willem S.; Verkade, Henkjan J.

    2015-01-01

    In pediatric acute liver failure (PALF), rapid referral to a transplant center (TC) is advocated. Clinical variability of PALF may influence referral timing. We aimed to analyze early or late timing of referral in relation to clinical characteristics and outcome in PALF. We conducted a

  16. Hepatitis A related acute liver failure by consumption of contaminated food

    NARCIS (Netherlands)

    Chi, Heng; Haagsma, Elizabeth B.; Riezebos-Brilman, Annelies; van den Berg, Arie P.; Metselaar, Herold J.; de Knegt, Robert J.

    2014-01-01

    We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the

  17. Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

    NARCIS (Netherlands)

    Engelmann, G.; Meyburg, J.; Shahbek, N.; Al-Ali, M.; Hairetis, M.H.; Baker, A.J.; Rodenburg, R.J.T.; Wenning, D.; Flechtenmacher, C.; Ellard, S.; Smeitink, J.A.M.; Hoffmann, G.F.; Buchanan, C.R.

    2008-01-01

    A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopath

  18. Quantitative multivoxel H-1 MR spectroscopy of the brain in children with acute liver failure

    NARCIS (Netherlands)

    Sijens, Paul E.; Alkefaji, Heyder; Lunsing, Roelineke J.; van Spronsen, Francjan J.; Meiners, Linda C.; Oudkerk, Matthijs; Verkade, Henkjan J.

    2008-01-01

    Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) an

  19. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Murphy, Nicholas; Brown, Sarah

    2016-01-01

    BACKGROUND & AIMS: Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a p...

  20. Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure

    DEFF Research Database (Denmark)

    Dao, Doan Y; Seremba, Emmanuel; Ajmera, Veeral;

    2012-01-01

    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....

  1. Prevention and management of brain edema in patients with acute liver failure

    DEFF Research Database (Denmark)

    Wendon, J.; Larsen, Finn Stolze

    2008-01-01

    1. Intracranial pressure is the pressure exerted by the cranial contents on the dural envelope and consists of the partial pressures of the brain, blood, and cerebrospinal fluid. 2. Severe cases of acute liver failure are frequently complicated by brain edema (due to cytotoxic edema...

  2. Hepatitis A related acute liver failure by consumption of contaminated food

    NARCIS (Netherlands)

    Chi, Heng; Haagsma, Elizabeth B.; Riezebos-Brilman, Annelies; van den Berg, Arie P.; Metselaar, Herold J.; de Knegt, Robert J.

    2014-01-01

    We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the

  3. Prometheus--a new extracorporeal system for the treatment of liver failure.

    Science.gov (United States)

    Rifai, Kinan; Ernst, Thomas; Kretschmer, Ulrich; Bahr, Matthias J; Schneider, Andrea; Hafer, Carsten; Haller, Hermann; Manns, Michael P; Fliser, Danilo

    2003-12-01

    Extracorporeal detoxification systems for supportive therapy of liver failure have recently gained much interest. We herein report results from the first clinical application of Prometheus, a new liver support system in which albumin-bound substances are directly removed from blood by special adsorber. In a simultaneous step, high-flux hemodialysis is performed. We assessed safety, adsorber efficiency and clinical efficacy of the Prometheus system. Eleven patients with acute-on-chronic liver failure and accompanying renal failure were treated with Prometheus on 2 consecutive days for >4 h. Prometheus treatment significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. There were no significant changes in hemoglobin and platelet levels, whereas leucocytes increased without signs of systemic infection. No treatment-related complications except a blood pressure drop in two patients with systemic infection were noted. In one patient (Child-Pugh score: 15) Prometheus treatment could not be completed due to onset of uncontrolled bleeding 16 h after dialysis. Prometheus is a safe supportive therapy for patients with liver failure. A significant improvement of the biochemical milieu was observed already after two treatments. Prospective controlled studies with the Prometheus system are necessary to evaluate hard clinical end-points.

  4. [Correction of cronic liver failure by transplantation of liver cells suspension and cell-engineering designs (experimental investigation)].

    Science.gov (United States)

    Got'e, S V; Shagidulin, M Iu; Onishchenko, N A; Krasheninnikov, M E; Il'inskiĭ, I M; Mozheĭko, N P; Liundup, A V; Volkova, E A; Petrakov, K I; Avramov, P V; Perova, N V; Sevast'ianov, V I

    2013-01-01

    On an experimental model of chronic fibrotic liver damage (male rats Wistar (n-60), damage of CCl4, the duration of the experiment 90 days) it was studied the effectiveness of cell therapy for the correction of chronic liver failure. These rats were divided into 3 experimental groups: in the Ist-group (control, n=10) isotonic saline (650 mkl.) was injected; in the IInd-group (n=20) suspension of liver cells was applicated in a dose 8 - l0 x 10(6) cells; in the IIIrd-group (n=30) suspension of liver cells and bone marrow cells (mesenchymal stromal cells) in ratio 5:1 were used as cell associates on microparticles intjectable heterogeneous biopolymer hydrogel "SpheroGEL" (cell-engineering design) in common dose 8 - l0 x 10(6) It was ascertained that in the 2nd and in the 3rd groups the accelerated normalization of disturbed liver functional indices (ALT, AST, ALP) took place - to 30 days, but in the control group only to 90 days. The reliable differences in rats ofnormalization offunctional indices were absent between the IInd and the IIIrd groups. But in 90 days by using special histological dyeing it was found out that defibrotic processes in liver tissue were more expressed in the IIIrd group in comparison with the IIIrd group. Received results were consequence of prolonged vital activity of cells (liver cells and mesenchymal stromal bone marrow cells) into cell-engineering designs, which were transplanted in the IIIrd group. The obtained effect can be explained by that the developed cell-engineering designs provide adequate conditions for prolonged vital activity of the transplanted cells.

  5. Lifesaving liver transplantation for multi-organ failure caused by Bacillus cereus food poisoning.

    Science.gov (United States)

    Tschiedel, Eva; Rath, Peter-Michael; Steinmann, Jörg; Becker, Heinz; Dietrich, Rudolf; Paul, Andreas; Felderhoff-Müser, Ursula; Dohna-Schwake, Christian

    2015-02-01

    Bacillus cereus is a spore-forming, gram-positive bacterium that causes food poisoning presenting with either emesis or diarrhea. Diarrhea is caused by proteinaceous enterotoxin complexes, mainly hemolysin BL, non-hemolytic enterotoxin (NHE), and cytotoxin K. In contrast, emesis is caused by the ingestion of the depsipeptide toxin cereulide, which is produced in B. cereus contaminated food, particularly in pasta or rice. In general, the illness is mild and self-limiting. However, due to cereulide intoxication, nine severe cases with rhabdomyolysis and/or liver failure, five of them lethal, are reported in literature. Here we report the first case of life-threatening liver failure and severe rhabdomyolysis in this context that could not be survived without emergency hepatectomy and consecutive liver transplantation.

  6. Severe acute haemorrhagic liver failure in a neonate with a favourable spontaneous outcome

    Energy Technology Data Exchange (ETDEWEB)

    Cavet, Madeleine; Balu, Marie; Garel, Catherine; Ducou le Pointe, Hubert [Universite Pierre et Marie Curie Paris VI, Service de Radiologie, Hopital d' enfants Armand-Trousseau, Paris (France); Mitanchez, Delphine; Alexandre, Marie [Universite Pierre et Marie Curie Paris VI, Service de Neonatologie, Hopital d' enfants Armand-Trousseau, Paris (France); Renolleau, Sylvain [Universite Pierre et Marie Curie Paris VI, Service de Reanimation, Hopital d' enfants Armand-Trousseau, Paris (France); Pariente, Daniele [Hopital de Bicetre, Service de Radiologie Pediatrique, Paris (France)

    2008-10-15

    Acute liver failure in neonates is rare and is frequently associated with an unfavourable outcome. There is no curative treatment other than liver transplantation. Screening for viral, metabolic, toxic or vascular disease is essential to assess the prognosis and to guide specific treatment. Hepatic haemorrhage in neonates is often associated with bacterial infection, trauma and coagulopathies. We present a unique case of neonatal acute liver failure and multifocal massive haemorrhagic intrahepatic lesions of traumatic origin, documented by US and MRI. The patient made a spontaneous recovery. Clinical, biological and imaging outcome was excellent despite the apparent severity of the initial features. The only possible aetiology was a difficult caesarean delivery for mild fetal macrosomia. (orig.)

  7. Acute liver failure at 26 weeks' gestation in a patient with sickle cell disease.

    Science.gov (United States)

    Greenberg, Mara; Daugherty, Tami J; Elihu, Arvand; Sharaf, Ravi; Concepcion, Waldo; Druzin, Maurice; Esquivel, Carlos O

    2009-10-01

    Orthotopic liver transplantation (OLT) for acute liver failure (ALF) during pregnancy is an uncommon occurrence with variable outcomes. In pregnancy-related liver failure, prompt diagnosis and immediate delivery are essential for a reversal of the underlying process and for maternal and fetal survival. In rare cases, the reason for ALF during pregnancy is either unknown or irreversible, and thus OLT may be necessary. This case demonstrates the development of cryptogenic ALF during the 26th week of pregnancy in a woman with sickle cell disease. She underwent successful cesarean delivery of a healthy male fetus at 27 weeks with concurrent OLT. This report provides a literature review of OLT in pregnancy and examines the common causes of ALF in the pregnant patient. On the basis of the management and outcome of our case and the literature review, we present an algorithm for the suggested management of ALF in pregnancy.

  8. Hepatocyte IKK2 protects Mdr2-/- mice from chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Hanno Ehlken

    Full Text Available Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2(-/- develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC. Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR transgene in hepatocytes was shown to prevent HCC development in Mdr2(-/- mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2(-/- mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2(-/- mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2(-/-IKK2(Hep-KO mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs.IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure.

  9. Longterm outcomes of auxiliary partial orthotopic liver transplantation in preadolescent children with fulminant hepatic failure.

    Science.gov (United States)

    Weiner, Joshua; Griesemer, Adam; Island, Eddie; Lobritto, Steven; Martinez, Mercedes; Selvaggi, Gennaro; Lefkowitch, Jay; Velasco, Monica; Tryphonopoulos, Panagiotis; Emond, Jean; Tzakis, Andreas; Kato, Tomoaki

    2016-04-01

    By preserving part of the native liver, auxiliary partial orthotopic liver transplantation (APOLT) provides the advantage of potential immunosuppression (ISP) withdrawal if the native liver recovers but has had limited acceptance, especially in the United States, due to technical complications and low rates of native liver regeneration. No previous study has evaluated APOLT specifically for preadolescent children with fulminant hepatic failure (FHF). This population might benefit especially based on greater capacity for liver regeneration. Data from 13 preadolescent children who underwent APOLT were compared to 13 matched controls who underwent orthotopic liver transplantation (OLT) for FHF from 1996 to 2013. There were no significant differences in patient demographics or survival between the 2 groups. However, all surviving OLT recipients (10/13) remain on ISP, while all but 1 surviving APOLT recipient (12/13) showed native liver regeneration, and the first 10 recipients (76.9%) are currently off ISP with 2 additional patients currently weaning. In our experience, APOLT produced excellent survival and high rates of native liver regeneration in preadolescent children with FHF. This represents the largest series to date to report such outcomes. Liberating these children from lifelong ISP without the downside of increased surgical morbidity makes APOLT an attractive alternative. In conclusion, we therefore propose that, with the availability of technical expertise and with the technical modifications above, APOLT for FHF should be strongly considered for preteenage children with FHF.

  10. Herpes Simplex Virus Hepatitis in an Immunocompetent Adult: A Fatal Outcome due to Liver Failure

    Directory of Open Access Journals (Sweden)

    Rachel A. Poley

    2011-01-01

    Full Text Available Objective. To present a case of a healthy 41-year-old female who developed fulminant hepatic failure leading to death. The cause of hepatic failure identified on postmortem exam was herpes simplex virus hepatitis. Design. Observation of a single patient. Setting. Intensive care unit of a tertiary care university teaching hospital in Canada. Patient. 41-year-old previously healthy female presenting with a nonspecific viral illness and systemic inflammatory response syndrome. Intervention. The patient was treated with intravenous fluids and broad-spectrum antibiotics. On the second day of admission, she was found to have elevated transaminases, and, over 48 hours, she progressed to fulminant liver failure with disseminated intravascular coagulopathy, refractory lactic acidosis, and shock. She progressed to respiratory failure requiring intubation and mechanical ventilation. She was started on N-acetylcysteine, a bicarbonate infusion, hemodialysis, and multiple vasopressors and inotropes. Measurements and Main Results. Despite treatment, the patient died roughly 70 hours after her initial presentation to hospital. Her postmortem liver biopsy revealed herpes simplex virus hepatitis as her cause of death. Conclusions. Herpes simplex virus must be considered in all patients presenting with liver failure of unknown cause. If suspected, prompt treatment with acyclovir should be initiated.

  11. An Unusual Presentation of Liver Failure in a Patient with Primary Gastrointestinal Hodgkin's Lymphoma

    Directory of Open Access Journals (Sweden)

    Gabrielle B. Rocque

    2011-01-01

    Full Text Available Introduction. Hodgkin's lymphoma (HL presenting either with primary bowel involvement or with cholestasis is unusual. The combination of primary gastrointestinal HL presenting with cholestasis and ductopenia has not been previously described. Case Report. We present a case of primary gastrointestinal HL with evidence of liver involvement, but also with prominent ductopenia on liver biopsy and associated intrahepatic cholestasis. A 50-year-old man with a history of Crohn's disease presented with a bowel obstruction, for which he underwent a small bowel resection. Histology revealed HL. His course was complicated by cholestatic liver failure. A subsequent liver biopsy revealed both focal involvement by lymphoma and ductopenia, resembling vanishing bile duct syndrome (VBDS. He was treated with chemotherapy with improvement in his cholestasis, but he eventually succumbed due to further complications of his disease and treatment toxicities. Conclusion. This case of primary gastrointestinal HL associated with ductopenia does not meet classic criteria for VBDS, but the clinical presentation and pathology are suggestive of a VBDS-like paraneoplastic process. Therapies for HL in the setting of cholestatic liver failure require special consideration, but some reports of durable remissions and recovery of liver function have been reported.

  12. Early renal failure after domino liver transplantation using organs from donors with primary hyperoxaluria type 1.

    Science.gov (United States)

    Saner, Fuat H; Treckmann, Juergen; Pratschke, Johann; Arbogast, Helmut; Rahmel, Axel; Vester, Udo; Paul, Andreas

    2010-10-15

    Organ shortage is responsible for high mortality rates of patients awaiting liver transplantation (LT). Domino transplantation has had reported success in patients with metabolic disorders. Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder. There are a few case reports that suggest that PH1 livers originating from donors that have undergone combined liver-kidney transplantation can be successfully used for domino transplantation. In the last decade, five patients received a domino liver transplant from patients with PH1 in the EUROTRANSPLANT region. In this study, we report the clinical course and outcome of these five patients who were received a domino graft transplant. All patients, with the exception of one, suffered from multifocal hepatocellular carcinoma and underwent domino LT from patients undergoing combined liver-kidney transplantation for PH1. Within the first 4 weeks, all the domino recipients developed dialysis-dependent kidney failure despite good liver function. Four of the five patients died. The only survivor underwent retransplantation due to hepatic artery thrombosis. Twenty months after transplantation, this patient is doing well and has had no recurrence of hepatocellular carcinoma. Domino LT using donors with PH1 results in early renal failure and cannot be recommended for transplantation unless preventive strategies have been identified.

  13. Severe Sarcopenia and Increased Fat Stores in Pediatric Patients With Liver, Kidney, or Intestine Failure.

    Science.gov (United States)

    Mangus, Richard S; Bush, Weston J; Kubal, Chandrashekhar A; Miller, Christina

    2017-06-09

    Malnutrition and wasting predict clinical outcomes in children with severe chronic illness. Objectively calculated malnutrition in children with end-stage organ failure has not been well studied. This analysis compares children with kidney, liver or intestine failure to healthy controls to quantitate the disparity in muscle and fat stores. Children younger than age 19 with end stage liver, kidney or intestine failure and with pre-transplant computed tomography (CT) imaging were selected from the transplant database. Age and gender-matched healthy controls were selected from the trauma database. Measures of nutrition status included a scaled scoring of core muscle mass, and visceral and subcutaneous fat stores. Analysis was conducted using the pooled and individually matched subject-control differences. There were 81 subjects included in the final analysis (liver (n = 35), kidney (n = 20) and intestine (n = 26)). Children with end-stage liver disease had a 23% reduction in muscle mass, a 69% increase in visceral fat and a 29% increase in subcutaneous fat. End-stage renal disease patients had a 19% reduction in muscle mass and a 258% increase in subcutaneous fat. Intestine failure patients had a 24% reduction in muscle mass, a 30% increase in visceral fat and a 46% increase in subcutaneous fat. These results demonstrate significant sarcopenia and increased fat stores in end-stage organ failure patients which supports the idea of an active physiologic mechanism to store fat while losing muscle mass. Sarcopenia may be related to total protein loss from a catabolic state, or from decreased synthesis (liver), wasting (kidney) or malabsorption (intestine).

  14. Effect of sesame oil against acetaminophen-induced acute oxidative hepatic damage in rats.

    Science.gov (United States)

    Chandrasekaran, Victor Raj Mohan; Wan, Chang-Hsin; Liu, Li-Lian; Hsu, Dur-Zong; Liu, Ming-Yie

    2008-08-01

    Acetaminophen (APAP) overdose causes acute liver injury or even death in both humans and experimental animals. We investigated the effect of sesame oil on APAP-induced acute liver injury. Male Wistar rats were given APAP (1,000 mg/kg; orally) to induce acute liver injury. Acetaminophen significantly increased aspartate transaminase, alanine transaminase, lipid peroxidation, and superoxide anion and hydroxyl radical generation levels; it also induced glutathione depletion. Sesame oil (8 mL/kg; orally) did not alter the gastric absorption of APAP, but it inhibited all the parameters altered by APAP and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil maintained the intracellular glutathione levels, reduced reactive oxygen species levels, and inhibited lipid peroxidation in rats with APAP-induced acute liver injury.

  15. Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potential New Mechanism of Liver Dysfunction and Failure during Sepsis?

    Science.gov (United States)

    Ehler, Johannes; Wagner, Nana-Maria

    2017-01-01

    Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for 2 × 72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey's test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P < 0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P < 0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients. PMID:28255555

  16. Acute Liver Failure: Pathophysiologic Basis, and The Current and Emerging Therapies

    Directory of Open Access Journals (Sweden)

    Graziella Privitera

    2014-05-01

    Full Text Available Acute liver failure (ALF is a devastating condition that occurs in patients who previously had a normal liver. Although the outcome of patients with ALF has improved, without liver transplantation (LT mortality rates remain in the range of 35-50% in different geographical areas and therefore, its treatment remains an unmet need. In the Western world toxic liver injury from acetaminophen remains one of the common causes but, in the East, hepatitis of unknown aetiology remains the most common cause. Treatment options are limited to meticulous attention to multi-organ support, use of N-acetyl cysteine, judicious use of antibiotics, and timely LT. This review describes the state-of-the-art techniques in the issues related to prognosis, outcome, and treatment of this devastating syndrome.

  17. Characteristics and Discrepancies in Acute-on-Chronic Liver Failure: Need for a Unified Definition.

    Directory of Open Access Journals (Sweden)

    Tae Yeob Kim

    Full Text Available To investigate the prevalence, mortalities, and patient characteristics of Acute-on-chronic liver failure (ACLF according to the AARC (Asian Pacific Association for the Study of the Liver ACLF Research Consortium and European Association for the Study of the Liver CLIF-C (Chronic Liver Failure Consortium definitions.We collected retrospective data for 1470 hospitalized patients with chronic liver disease (CLD and acute deterioration between January 2013 and December 2013 from 21 university hospitals in Korea.Of the patients assessed, the prevalence of ACLF based on the AARC and CLIF-C definitions was 9.5% and 18.6%, respectively. The 28-day and 90-day mortality rates were higher in patients with ACLF than in those without ACLF. Patients who only met the CLIF-C definition had significantly lower 28-day and 90-day survival rates than those who only met the AARC definition (68.0% vs. 93.9%, P<0.001; 55.1% vs. 92.4%, P<0.001. Among the patients who had non-cirrhotic CLD, the 90-day mortality of the patients with ACLF was higher than of those without ACLF, although not significant (33.3% vs. 6.0%, P = 0.192. Patients with previous acute decompensation (AD within 1- year had a lower 90-day survival rate than those with AD more than 1 year prior or without previous AD (81.0% vs. 91.9% or 89.4%, respectively, all P<0.001. Patients who had extra-hepatic organ failure without liver failure had a similar 90-day survival rate to those who had liver failure as a prerequisite (57.0% vs. 60.6%, P = 0.391.The two ACLF definitions result in differences in mortality and patient characteristics among ACLF patients. We suggest that non-cirrhotic CLD, previous AD within 1 year, and extra-hepatic organ failure should be included in the ACLF diagnostic criteria. In addition, further studies are necessary to develop a universal definition of ACLF.

  18. Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients.

    Science.gov (United States)

    Kondo, Kazuma; Yamada, Naohito; Suzuki, Yusuke; Toyoda, Kaoru; Hashimoto, Tatsuji; Takahashi, Akemi; Kobayashi, Akio; Shoda, Toshiyuki; Kuno, Hideyuki; Sugai, Shoichiro

    2012-01-01

    Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500mg/kg and hepatic function parameters were increased at 300 and 500mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

  19. Effects of sesame oil against after the onset of acetaminophen-induced acute hepatic injury in rats.

    Science.gov (United States)

    Chandrasekaran, Victor Raj Mohan; Chien, Se-Ping; Hsu, Dur-Zong; Chang, Yu-Chung; Liu, Ming-Yie

    2010-01-01

    Acetaminophen (APAP) is a safe and effective analgesic and antipyretic when used at therapeutic levels. However, an acute or cumulative overdose can cause severe liver injury with the potential to progress to liver failure in humans and experimental animals. Much attention has been paid to the development of an antioxidant that protects against APAP-induced acute hepatic injury. Hence, we aimed to investigate the effect of sesame oil against after the onset of acute hepatic injury in APAP-overdosed rats. Male Wistar rats were first given 2 oral doses (1,000 mg/kg each) of APAP (at 0 and 24 hours) and then 1 oral dose of sesame oil (8 mL/kg at 24 hours). After 48 hours, APAP increased aspartate and alanine aminotransferase levels in the rats' serum and centrilobular necrosis in liver tissue. In addition, APAP significantly decreased the rats' glutathione levels and mitochondrial aconitase activity, but increased superoxide anion, hydroxyl radical, and lipid peroxidation levels. Oral sesame oil (8 mL/kg, given at 24 hours) reversed all APAP-altered parameters and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil acts as a useful agent that maintains intracellular glutathione levels and inhibits reactive oxygen species, thereby protecting rats against after the onset of APAP-induced acute oxidative liver injury.

  20. Acute liver failure in Chinese children:a multicenter investigation

    Institute of Scientific and Technical Information of China (English)

    Pan Zhao; Chun-Ya Wang; Wei-Wei Liu; Xi Wang; Li-Ming Yu and Yan-Rong Sun

    2014-01-01

    BACKGROUND: Currently,  no  documentation  is  available regarding Chinese children with acute liver failure (ALF). This study was undertaken to investigate etiologies and outcomes of Chinese children with ALF. METHODS: We retrospectively enrolled 32 pediatric patients with  ALF  admitted  in  ifve  hospitals  in  different  areas  of China from January 2007 to December 2012. The coagulation indices,  serum  creatinine,  serum  lactate  dehydrogenase, blood ammonia and prothrombin activity were analyzed; the relationship between these indices and mortality was evaluated by multivariate analysis. RESULTS: The most common causes of Chinese children with ALF were indeterminate etiology (15/32), drug toxicity (8/32), and acute cytomegalovirus hepatitis (6/32). Only 1 patient (3.13%) received liver transplantation and the spontaneous mortality of Chinese children with ALF was 58.06% (18/31). Patients who eventually died had higher baseline levels of international normalized ratio (P=0.01), serum creatinine (P=0.04), serum lactate dehydrogenase (P=0.01), blood ammonia (P CONCLUSIONS: The indeterminate causes predominated in the etiologies of ALF in Chinese children. The spontaneous mortality of pediatric patients with ALF was high, whereas the proportion of patients undergoing liver transplantation was signiifcantly low. Entry blood ammonia was a reliable predictor for the death of pediatric patients with ALF.

  1. Acute liver failure due to Human Herpesvirus 6 in an infant

    Directory of Open Access Journals (Sweden)

    G.M. Tronconi

    2012-10-01

    Full Text Available We report a case of a 4-months infant with fever in the absence of other specific symptoms that has rapidly and unexpectedly developed acute liver failure (ALF with coagulopathy and complicated with bone marrow failure without encephalopathy. The main viral infection agents (hepatitis virus A, B, C, Citomegalovirus, Ebstain Barr virus, Parvovirus B19, Adenovirus, drug-induced hepatotoxicity and metabolic disorders associated to ALF were excluded. Quantitative determination of Human Herpesvirus 6 (HHV6 genome was positive with a significant number of copies for mL. A favorable evolution of the clinical symptoms and a progressive hematochemical resolution were obtained. Plasma and Vitamin K were administrated as a support therapy for treating coagulopathy. The present case report and the cases’ review from the literature, evidence the importance of always including screening for HHV6 infection in the diagnostic approach to acute onset of liver failure. HHV6 is a common virus in the pediatric population with a greater number of cases of fulminant viral non-A, non-B, non-C hepatitis in immunocompetent patients due to this virus: these forms have often a high mortality rate and maybe necessitate liver transplantation; for this reason correct etiological agent identification is mandatory for the prognosis and it has to be based on the quantitative search of the virus’s genome. Pathogenesis of liver-induced damage associated to HHV6 remains unclear; however in vitro studies demonstrate the potential hepatotoxicity effects of this virus.

  2. [Acute liver failure due to human herpesvirus 6 in an infant].

    Science.gov (United States)

    Tronconi, G M; Mariani, B; Pajno, R; Fomasi, M; Cococcioni, L; Biffi, V; Bove, M; Corsin, P; Garbetta, G; Barera, G

    2012-01-01

    We report a case of a 4-months infant with fever in the absence of other specific symptoms that has rapidly and unexpectedly developed acute liver failure (ALF) with coagulopathy and complicated with bone marrow failure without encephalopathy. The main viral infection agents (hepatitis virus A, B, C, Citomegalovirus, Ebstain Barr virus, Parvovirus B19, Adenovirus), drug-induced hepatotoxicity and metabolic disorders associated to ALF were excluded. Quantitative determination of Human Herpesvirus 6 (HHV6) genome was positive with a significant number of copies for mL. A favorable evolution of the clinical symptoms and a progressive hematochemical resolution were obtained. Plasma and Vitamin K were administrated as a support therapy for treating coagulopathy. The present case report and the cases' review from the literature, evidence the importance of always including screening for HHV6 infection in the diagnostic approach to acute onset of liver failure. HHV6 is a common virus in the pediatric population with a greater number of cases of fulminant viral non-A, non-B, non-C hepatitis in immunocompetent patients due to this virus: these forms have often a high mortality rate and maybe necessitate liver transplantation; for this reason correct etiological agent identification is mandatory for the prognosis and it has to be based on the quantitative search of the virus's genome. Pathogenesis of liver-induced damage associated to HHV6 remains unclear; however in vitro studies demonstrate the potential hepatotoxicity effects of this virus.

  3. Analyses of prognostic indices of chronic liver failure caused by hepatitis virus

    Institute of Scientific and Technical Information of China (English)

    Xiao-Mao Li; Lin Ma; Yue-Bo Yang; Zhong-Jie Shi; Shui-Sheng Zhou

    2005-01-01

    AIM: To analyze the related indices about the prognosesof chronic liver failure caused by hepatitis virus.METHODS: Retrospectively reviewed 320 cases of chronic liver failure caused by hepatitis viruses. An improved group and an ineffective group (IG) were made to compare and analyze their clinical manifestations, laboratory examination indices and complications. Logistic regression was also carried out. RESULTS: There were significant differences (P<0.05) between the improved group and the IG upon such indices as age, bilirubin, prothrombin time, albumin, alpha fetoprotein, the size of liver and complications (P<0.05). The regression formula was as follows: P = 1/(1+e-y)(y= 1.7262-0.0948X1+2.9846X2+0.6992X3+ 1.6019X4+2.0398X5). (Note: X1-Prothrombin activity; X2-digestive tract hemorrhage; X3-hepatic encephalopathy; X4-hepatorenal syndrome; X5-pulmonary infection.).CONCLUSION: Laboratory examination such as bilirubin, prothrombin time and alpha fetoprotein can be regarded as indices of the prognoses of chronic liver failure caused by hepatitis. Moreover, the regression equation can evaluate prognoses more comprehensively and direct our treatments.

  4. Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia

    Institute of Scientific and Technical Information of China (English)

    Masayuki Miyazaki; Masatake Tanaka; Akihiro Ueda; Tsuyoshi Yoshimoto; Masaki Kato; Makoto Nakamuta; Kazuhiro Kotoh; Ryoichi Takayanagi

    2011-01-01

    Drug-induced hypersensitivity syndrome (DIHS) is a se-vere reaction usually characterized by fever, rash, and multiorgan failure, occurring 2-6 wk after drug introduction.It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release. A 54-year-old woman was diagnosed with rheumatic arthritis and initiated salazosulfapyridine by mouth. About 10 d later, she had a high fever, skin rash and liver dysfunction. She was admitted to hospital and diagnosed with a drug eruption. She was treated with oral prednisolone 30 mg/d; however, she developed high fever again and her blood tests showed acute liver failure and cytopenia associated with hyperferritinemia. She was diagnosed with acute liver failure and hemophagocytosis caused by DIHS. She was transferred to the Department of Medicine and Bioregulatory Science, Kyushu University, where she was treated with arterial steroid injection therapy. Following this treatment, her liver function improved and serum ferritin immediately decreased. We hypothesized that an immune-mediated reaction in DIHS may have generated over-activation of macrophages and T-lymphocytes, followed by a cytokine storm that affected various organs. The measurement of serum ferritin might be a useful marker of the severity of DIHS.

  5. [Psychosocial indication of liver transplantation for alcohol-related liver failure: current controversies and imminent issues in Japanese society].

    Science.gov (United States)

    Kiuchi, Tetsuya

    2012-10-01

    Organ transplant therapy is becoming a usual practice also in Japan, which dramatically improves the length and quality of life in patients with end-stage organ disease. Liver transplantation was resumed in Japan much later than that in the West and is continued now under unique circumstances where more than 90% of grafts come from living donors. Nevertheless the number of liver transplantation for alcohol-related liver failure shows a sharp rise to the level comparable to the West, and not a few physical and/or psychosocial problems caused by recidivism after transplantation are coming up. To find appropriate solutions to how to predict recidivism and define psychosocial indication of liver transplantation in our society, and to how to monitor and support sobriety after transplantation, there is an urgent need for multidisciplinary management by hepatologist, transplant surgeon, psychiatrist, and dependence specialist. Life-saving therapy and dependence management are expected to work closely together from the viewpoints of transparency, equity, utility, and autonomy requested in transplant therapy, protection of living donors, and consideration for donor family and public emotion.

  6. Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support

    Science.gov (United States)

    Damania, Apeksha; Hassan, Mohsin; Shirakigawa, Nana; Mizumoto, Hiroshi; Kumar, Anupam; Sarin, Shiv K.; Ijima, Hiroyuki; Kamihira, Masamichi; Kumar, Ashok

    2017-01-01

    Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20–60% in the integrated bioreactor as opposed to 5–15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device. PMID:28079174

  7. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Hanafy, Abeer; Aldawsari, Hibah M; Badr, Jihan M; Ibrahim, Amany K; Abdel-Hady, Seham El-Sayed

    2016-01-01

    The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  8. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Abeer Hanafy

    2016-01-01

    Full Text Available The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  9. Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant

    Institute of Scientific and Technical Information of China (English)

    Tatehiro Kagawa; Kazuo Shimamura; Shohei Matsuzaki; Tetsuya Mine; Norihito Watanabe; Hisashi Kanouda; Ichiro Takayama; Tadahiko Shiba; Takashi Kanai; Kazuya Kawazoe; Shinji Takashimizu; Nobue Kumaki

    2004-01-01

    We report a case of fatal liver failure due to reactivation of lamivudine-resistant HBV. A 53-year-old man was followed since 1998 for HBV-related chronic hepatitis. Serum HBVDNA was 150 MEq/mL (branched DNA signal amplification assay) and ALT levels fluctuated between 50-200 IU/L with no clinical signs of liver cirrhosis. Lamivudine (100 mg/d)was started in May 2001 and serum HBV-DNA subsequently decreased below undetectable levels. In May 2002, serum HBV-DNA had increased to 410 MEq/mL, along with ALT flare (226 IU/L). The YMDD motif in the DNA polymerase gene had been replaced by YIDD. Lamivudine was continued and ALT spontaneously decreased to the former levels. On Oct 3 the patient presenting with general fatigue, nausea and jaundice was admitted to our hospital. The laboratory data revealed HBV reactivation and liver failure (ALT: 1828IU/L, total bilirubin: 10 mg/dL, and prothrombin INR: 3.24).For religious reasons, the patient and his family refused blood transfusion, plasma exchange and liver transplantation.The patient died 10 d after admission. The autopsy revealed remarkable liver atrophy.

  10. Diagnosis by routine scintigraphy of hepatic reticuloendothelial failure before severe liver dysfunction.

    Science.gov (United States)

    Shiomi, S; Kuroki, T; Ueda, T; Takeda, T; Nishiguchi, S; Nakajima, S; Kobayashi, K; Ochi, H

    1996-01-01

    The prognosis of hepatic reticuloendothelial failure is said to be poor. Scanning with the radiocolloid 99mTc phytate is needed for diagnosis; as a rule; only seriously ill patients are so investigated. We use 99mTc phytate for liver scans of almost all inpatients with liver disease. This routine made diagnosis of a mild form or early stage of the disease possible. We evaluated the clinical findings of the five patients we have diagnosed, in an attempt to find why four survived. Radiocolloid scans were taken starting 20-30 min after the intravenous injection of 111 MBq of 99mTc phytate. Hepatobiliary images were taken by use of 99mTc pyridoxylidine-5-methyl trytophan, and hepatic receptor images were taken by use of 99mTc-labeled diethylenetriaminepentaacetic acid coupled with galactosyl human serum albumin. The livers were not visible in the radiocolloid scans, so the diagnosis of hepatic reticuloendothelial failure was considered. In the two other imaging examinations, the livers were visible. The cause was identified as heavy alcohol intake in four cases and toluene hepatotoxicity in one case. Histological examinations showed cirrhosis in two patients; the three other patients did not have cirrhosis. All five patients had anemia, and three had infections. One patient died of multiple organ failure, and the four other patients survived. Long-term observation by radiocolloid scanning was possible in one patient in whom radionuclide uptake into the liver rose as hepatic function improved. This disorder is associated with a temporary decrease in Kupffer cell function and hence is liable to be complicated by infection, which can result in death. If the cause is removed promptly, recovery is likely. There being a mild form of this disease, previously not generally diagnosed, probably accounts for the outcomes being good in all of our patients except the one patient with severe liver dysfunction at the time of diagnosis.

  11. [Early detection, prevention and management of renal failure in liver transplantation].

    Science.gov (United States)

    Castells, Lluís; Baliellas, Carme; Bilbao, Itxarone; Cantarell, Carme; Cruzado, Josep Maria; Esforzado, Núria; García-Valdecasas, Juan Carlos; Lladó, Laura; Rimola, Antoni; Serón, Daniel; Oppenheimer, Federico

    2014-10-01

    Renal failure is a frequent complication in liver transplant recipients and is associated with increased morbidity and mortality. A variety of risk factors for the development of renal failure in the pre- and post-transplantation periods have been described, as well as at the time of surgery. To reduce the negative impact of renal failure in this population, an active approach is required for the identification of those patients with risk factors, the implementation of preventive strategies, and the early detection of progressive deterioration of renal function. Based on published evidence and on clinical experience, this document presents a series of recommendations on monitoring RF in LT recipients, as well as on the prevention and management of acute and chronic renal failure after LT and referral of these patients to the nephrologist. In addition, this document also provides an update of the various immunosuppressive regimens tested in this population for the prevention and control of post-transplantation deterioration of renal function.

  12. Definitions of Acute-On-Chronic Liver Failure: The Past, the Present, and the Future

    Directory of Open Access Journals (Sweden)

    Roland Amathieu

    2015-01-01

    Full Text Available Acute-on-chronic liver failure (ACLF is an entity used to define patients with liver cirrhosis presenting with acute decompensation. For over 20 years, ACLF has taken multiple definitions and/or classifications. Unfortunately, to date, there has not been a universally accepted definition/classification of this entity. In this short review, we discuss the definition evolution of ACLF, the strengths and weaknesses of the existing definitions and classifications, and finally the potential role of the ‘omic’ approaches for the diagnosis of this complex syndrome.

  13. The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity.

    Science.gov (United States)

    Lee, Da Hyun; Park, Jeong Su; Lee, Yu Seol; Sung, Su Haeng; Lee, Yong-Ho; Bae, Soo Han

    2017-02-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity. [BMB Reports 2017; 50(2): 91-96].

  14. Functional renal failure (FRF) in cirrhosis of the liver and liver carcinoma

    Science.gov (United States)

    Vesin, P.; Traverso, H.

    1975-01-01

    The term ‘functional renal failure’ has been used to describe the renal failure developing in advanced cirrhosis in which tubular function and structure remain intact. It may develop spontaneously, in which case prognosis is poor, but may be secondary to gastro-intestinal haemorrhage or excessive use of diuretics, in which case correction of the precipitating factor leads to improvement in renal function. It is suggested that the renal failure is due to a reduction in effective circulating plasma volume. PMID:1234327

  15. xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway.

    Science.gov (United States)

    Kang, Eun Sil; Lee, Jaeyong; Homma, Takujiro; Kurahashi, Toshihiro; Kobayashi, Sho; Nabeshima, Atsunori; Yamada, Sohsuke; Seo, Han Geuk; Miyata, Satoshi; Sato, Hideyo; Fujii, Junichi

    2017-01-01

    Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the transsulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine γ-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT(-/-) mice was increased to a greater extent than that for the xCT(+/+) mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT(+/+) and xCT(-/-) mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems.

  16. Saponins (Ginsenosides) from the Leaves of Panax quinquefolius Ameliorated Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Xu, Xing-Yue; Hu, Jun-Nan; Liu, Zhi; Zhang, Rui; He, Yu-Fang; Hou, Wei; Wang, Zhi-Qing; Yang, Ge; Li, Wei

    2017-05-10

    Acetaminophen (APAP) overdose is one of the most common inducements of drug-induced liver injury (DILI) in the world. The main purpose of this paper was to investigate the liver protection activity of saponins (ginsenosides) from the leaves of Panax quinquefolius (PQS) against APAP-induced hepatotoxicity, and the involved mechanisms were demonstrated for the first time. Mice were pretreated with PQS (150 and 300 mg/kg) by oral gavage for 7 days before being treated with 250 mg/kg APAP. Severe liver injury was exerted at 24 h post-APAP, and hepatotoxicity was assessed. Our results showed that pretreatment with PQS significantly decreased the serum alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β) levels in a dose-dependent manner as compared to the APAP administration. Meanwhile, compared with that in the APAP group, PQS decreased hepatic malondialdehyde (MDA) contents and 4-hydroxynonenal (4-HNE) expression and restored reduced glutathione (GSH) content and superoxide dismutase (SOD) activity in livers of mice. PQS inhibited the overexpression of pro-inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the liver tissues. Furthermore, Western blotting analysis revealed that PQS pretreatment inhibited the activation of apoptotic signaling pathways via increase of Bcl-2 and decrease of Bax and caspase-3 protein expression levels. Liver histopathological observation provided further evidence that PQS pretreatment significantly inhibited APAP-induced hepatocyte necrosis, inflammatory cell infiltration, and congestion. Biological indicators of nitrative stress such as 3-nitrotyrosine (3-NT) were inhibited after PQS pretreatment, compared to the APAP group. The present study clearly demonstrates that PQS exerts a protective effect against APAP-induced hepatic injury because of its antioxidant, anti-apoptotic, and anti-inflammatory activities. The findings from

  17. Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy.

    Directory of Open Access Journals (Sweden)

    Rekha Gautam

    Full Text Available Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/- mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/- mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.

  18. Fatal liver failure caused by reactivation of lamivudine-resistant hepatitis B virus: A case report

    Institute of Scientific and Technical Information of China (English)

    Yuka Suzuki; Fumio Itoh; Hiroshi Yotsuyanagi; Chiaki Okuse; Yoshihiko Nagase; Hideaki Takahashi; Kyoji Moriya; Michihiro Suzuki; Kazuhiko Koike; Shiro lino

    2007-01-01

    We present a case of fetal liver failure caused by the activation of lamivudine-resistant hepatitis B virus (HBV) nine months after lamivudine treatment. A 57-year old man visited our hospital for the treatment of decompensated chronic hepatitis B. Lamivudine was started in December 2001. Subsequently, serum HBV was negative for HBV DNA with seroconversion from HBeAg to anti-HBe and improvement of liver function. However, HBV DNA and HBeAg were again detected in September 2002. He was complicated by breakthrough hepatitis and admitted to our hospital in November for severely impaired liver function. Vidarabine treatment was started and serum HBV DNA and alanine aminotransferase (ALT) decreased transiently. However, after the start of a-interferon treatment, HBV DNA level increased and liver function deteriorated. He died 1 mo after admission. An analysis of amino acid sequences in the polymerase region revealed that rtM204I/V with rtL80I/V occurred at the time of viral breakthrough. After the start of antiviral treatment, rtL180M was detected in addition to rtM204I/V and rtL80I/V, and became predominant in the terminal stage of the disease. HBV clone with a high replication capacity may be produced by antiviral treatment leading to the worsening of liver function. Antiviral therapy for patients with breakthrough hepatitis in advanced liver disease should be carefully performed.

  19. CORRECTION OF MICROCIRCULATORY DISORDERS IN NON-ALCOHOLIC FATTY LIVER DISEASE IN PATIENTS WITH CHRONIC HEART FAILURE PATIENTS

    Directory of Open Access Journals (Sweden)

    M. E. Statsenko

    2016-01-01

    Full Text Available Combined liver damage in patients with chronic heart failure and non-alcoholic fatty liver disease leads to the formation of pathological hemodynamic types of microcirculation with prevalence of shunt blood flow, nutritional deficiency, that correlated with changes in the functional state of the liver. Using cytoprotector mexicor for 16 weeks as part of the basic treatment of patients with chronic heart failure and non-alcoholic fatty liver disease can correct these microcirculatory disorders, has a beneficial effect on endothelial function, autonomic tone of microvessels, which is accompanied by the positive dynamics of indicators of cytolysis and cholestasis.

  20. Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.

    Science.gov (United States)

    Piano, Salvatore; Tonon, Marta; Vettore, Elia; Stanco, Marialuisa; Pilutti, Chiara; Romano, Antonietta; Mareso, Sara; Gambino, Carmine; Brocca, Alessandra; Sticca, Antonietta; Fasolato, Silvano; Angeli, Paolo

    2017-07-19

    Acute-on-chronic liver failure (ACLF) is the most life-threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45±44months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1year, 5years, and 10years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p=0.012), ascites (HR 2.53; p=0.019), model of end-stage liver disease score (HR 1.26; p<0.001) and baseline hemoglobin (HR 0.07; p=0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to

  1. Acute liver failure in a pediatric patient with congenital dyserythropoietic anemia type I treated with deferasirox

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    Galina Ling

    2015-09-01

    Full Text Available Congenital dyserythropoietic anemias (CDA represent a heterogeneous group of disorders characterized by morphological abnormalities of erythroid precursor cells and various degrees of hemolysis. Iron overload is a result of continuous hemolysis and recurrent transfusions. It is treated with iron chelators, including deferasirox. We present here a case of acute liver failure in a 12 years old girl with CDA type I treated with deferasirox and discuss the approach to treatment.

  2. [Use of fractional plasma separation and adsorption (Prometheus technology) in the treatment of acute liver failure].

    Science.gov (United States)

    Denisova, E N; Sharipova, V R; Purlo, N V; Sukhanova, G A; Biriukova, L S

    2009-01-01

    This paper presents the results of treating 8 patients with acute liver failure, by using the separation and adsorption of fractional plasma (Prometheus technology). Twenty-five procedures lasting 5-6 hours were performed. Anticoagulation with heparin was made under guidance of coagulogram parameters. The results of testing blood parameters before and after a procedure and hemodynamic parameters are given. The investigations have demonstrated the effectiveness and safety of the procedure.

  3. Predictors of the outcomes of acute-on-chronic hepatitis B liver failure

    Institute of Scientific and Technical Information of China (English)

    Hsiu-Lung Fan; Po-Sheng Yang; Hui-Wei Chen; Teng-Wei Chen; De-Chuan Chan; Chi-Hong Chu; Jyh-Cherng Yu

    2012-01-01

    AIM:TO identify the risk factors in predicting the outcome of acute-on-chronic hepatitis B liver failure patients.METHODS:We retrospectively divided 113 patients with acute-on-chronic liver failure-hepatitis B virus (ACLF-HBV) and without concurrent hepatitis C or D virus infection and hepatocellular carcinoma into two groups according to their outcomes after anti-HBV therapy.Their demographic,clinical,and biochemical data on the day of diagnosis and after the first week of treatment were analyzed using the Mann-Whitney U test,Fisher's exact test,and a multiple logistic regression analysis.RESULTS:The study included 113 patients (87 men and 26 women) with a mean age of 49.84 years.Fiftytwo patients survived,and 61 patients died.Liver failure (85.2%),sepsis (34.4%),and multiple organ failure (39.3%) were the main causes of death.Multivariate analyses showed that Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ scores ≥ 12[odds ratio (OR) =7.160,95% CI:2.834-18.092,P <0.001] and positive blood culture (OR =13.520,95%CI:2.740-66.721,P =0.001) on the day of diagnosis and model for end-stage liver disease (MELD) scores ≥ 28 (OR =8.182,95% CI:1.884-35.527,P =0.005)after the first week of treatment were independent predictors of mortality.CONCLUSION:APACHE Ⅱ scores on the day of diagnosis and MELD scores after the first week of anti-HBV therapy are feasible predictors of outcome in ACLF-HBV patients.

  4. OUTCOME OF ACUTE LIVER FAILURE DUE TO HEPATITIS A TREATED WITH MEDICAL MANAGEMENT

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    Thulaseedharan Nallaveettil

    2016-02-01

    Full Text Available BACKGROUND Acute liver failure is a heterogeneous entity and its prognosis varies with the aetiology. In India and other developing countries, hepatitis A virus is an important cause of acute liver failure. The prognostic factors and outcome of such patients should be studied separately. AIM OF THE STUDY To study the outcome of patients with acute liver failure due to hepatitis A treated with intensive supportive care and to determine the prognostic factors predicting the transplant free survival. MATERIALS AND METHODS In this observational study, all patients admitted in our hospital with ALF due to hepatitis A virus infection during the period of 3 years from January 1st 2013 to December 31st 2015 were selected; 40 patients satisfied the inclusion and exclusion criteria. Detailed history taking, physical examination, haematological and biochemical investigations were performed. The day-to-day progress and treatment given until discharge or death were recorded. RESULTS Overall mortality in acute liver failure due to hepatitis A was 30%. Transplant free survival was 100% in patients with grade I and II encephalopathy, 66.6% in grade III encephalopathy and 22.2% in grade IV encephalopathy (P less than 0.001. Extrahepatic manifestations were observed in 29 patients (72.5%, the most common was thrombocytopenia in 22 patients (55% followed by acute kidney injury in 12 patients (30%. CONCLUSIONS The grade of hepatic encephalopathy was the single most important factor that determined the prognosis. Patients with grade I and II encephalopathy had 100% spontaneous survival rate.

  5. Dirofilaria repens in a cat with acute liver failure : case report

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    E.V. Schwan

    2000-07-01

    Full Text Available Acute liver failure was diagnosed in a 12-year-old cat. Fine needle aspirate cytology revealed high numbers of unsheathed microfilariae and a hepatocellular reaction with no evidence of bacterial infection. The microfilariae were identified as those of Dirofilaria repens by acid phosphatase staining. The high number of microfilariae seen in both the blood and the liver aspirate samples as well as the favourable response to ivermectin amongst other drugs administered, is suggestive that D. repens was the cause of the liver insult. A positive result obtained with an antigen-capture ELISA (Dirochek (r for Dirofilaria immitis antigen was interpreted as false. This is the 1st report of Dirofilaria repens for South Africa.

  6. Heterotopic auxiliary rat liver transplantation with flow-regulated portal vein arterialization in acute hepatic failure.

    Science.gov (United States)

    Schleimer, Karina; Kalder, Johannes; Grommes, Jochen; Jalaie, Houman; Tawadros, Samir; Greiner, Andreas; Jacobs, Michael; Kokozidou, Maria

    2014-01-01

    In acute hepatic failure auxiliary liver transplantation is an interesting alternative approach. The aim is to provide a temporary support until the failing native liver has regenerated.(1-3) The APOLT-method, the orthotopic implantation of auxiliary segments- averts most of the technical problems. However this method necessitates extensive resections of both the native liver and the graft.(4) In 1998, Erhard developed the heterotopic auxiliary liver transplantation (HALT) utilizing portal vein arterialization (PVA) (Figure 1). This technique showed promising initial clinical results.(5-6) We developed a HALT-technique with flow-regulated PVA in the rat to examine the influence of flow-regulated PVA on graft morphology and function (Figure 2). A liver graft reduced to 30 % of its original size, was heterotopically implanted in the right renal region of the recipient after explantation of the right kidney.  The infra-hepatic caval vein of the graft was anastomosed with the infrahepatic caval vein of the recipient. The arterialization of the donor's portal vein was carried out via the recipient's right renal artery with the stent technique. The blood-flow regulation of the arterialized portal vein was achieved with the use of a stent with an internal diameter of 0.3 mm. The celiac trunk of the graft was end-to-side anastomosed with the recipient's aorta and the bile duct was implanted into the duodenum. A subtotal resection of the native liver was performed to induce acute hepatic failure. (7) In this manner 112 transplantations were performed. The perioperative survival rate was 90% and the 6-week survival rate was 80%. Six weeks after operation, the native liver regenerated, showing an increase in weight from 2.3±0.8 g to 9.8±1 g. At this time, the graft's weight decreased from 3.3±0.8 g to 2.3±0.8 g. We were able to obtain promising long-term results in terms of graft morphology and function. HALT with flow-regulated PVA reliably bridges acute hepatic failure

  7. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

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    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  8. Loss and recovery of liver regeneration in rats with fulminant hepatic failure.

    Science.gov (United States)

    Eguchi, S; Lilja, H; Hewitt, W R; Middleton, Y; Demetriou, A A; Rozga, J

    1997-10-01

    We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass

  9. Metabonomic analysis of hepatitis B virus-induced liver failure: identification of potential diagnostic biomarkers by fuzzy support vector machine

    Institute of Scientific and Technical Information of China (English)

    Yong MAO; Xin HUANG; Ke YU; Hai-bin QU; Chang-xiao LIU; Yi-yu CHENG

    2008-01-01

    Hepatitis B virus (HBV)-induced liver failure is an emergent liver disease leading to high mortality. The severity of liver failure may be reflected by the profile of some metabolites. This study assessed the potential of using metabolites as biomarkers for liver failure by identifying metabolites with good discriminative performance for its phenotype. The serum samples from 24 HBV-induced liver failure patients and 23 healthy volunteers were collected and analyzed by gas chromatography-mass spectrometry (GC-MS) to generate metabolite profiles. The 24 patients were further grouped into two classes according to the severity of liver failure. Twenty-five commensal peaks in all metabolite profiles were extracted, and the relative area values of these peaks were used as features for each sample. Three algorithms, F-test, k-nearest neighbor (KNN) and fuzzy support vector machine (FSVM) combined with exhaustive search (ES), were employed to identify a subset of metabolites (biomarkers) that best predict liver failure. Based on the achieved experimental dataset, 93.62% predictive accuracy by 6 features was selected with FSVM-ES and three key metabolites, glyceric acid, cis-aconitic acid and citric acid, are identified as potential diagnostic biomarkers.

  10. Impact of preoperative chronic renal failure on liver transplantation: a population-based cohort study

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    Chung PC

    2016-12-01

    Full Text Available Peter Chi-Ho Chung,1,2 Hsiu-Pin Chen,1,2 Jr-Rung Lin,3,4 Fu-Chao Liu,1,2 Huang-Ping Yu1,2 1Department of Anesthesiology, Chang Gung Memorial Hospital, 2College of Medicine, 3Clinical Informatics and Medical Statistics Research Center, 4Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan Purpose: The purpose of this study was to assess whether preoperative chronic renal failure (CRF affects the rates of postoperative complications and survival after liver transplantation. Methods: This population-based retrospective cohort study included 2,931 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. Patients were divided into two groups, based on the presence or absence of preoperative CRF. Results: The overall estimated survival rate of liver transplantation recipients (LTRs with preoperative CRF was significantly lower than that of patients without preoperative CRF (P=0.0085. There was no significant difference between the groups in terms of duration of intensive care unit stay, total hospital stay, bacteremia, postoperative bleeding, and pneumonia during hospitalization. Long-term adverse effects, including cerebrovascular disease and coronary heart disease, were not different between patients with versus without CRF. Conclusion: These findings suggest that LTRs with preoperative CRF have a higher rate of mortality. Keywords: chronic renal failure, cohort study, survival rate, liver transplantation, population-based study

  11. Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity.

    Science.gov (United States)

    Uysal, Hilal Bektas; Dağlı, Bekir; Yılmaz, Mustafa; Kahyaoğlu, Fadime; Gökçimen, Alparslan; Ömürlü, İmran Kurt; Demirci, Buket

    2016-01-01

    The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 ± 0.210, 0.213 ± 0.004, 0.194 ± 0.001, 0.197 ± 0.06, 0.199 ± 0.008 and 0.173 ± 0.010 μmol/g protein, respectively. Total glutathione levels were 7.787 ± 0.395, 14.925 ± 0.932, 13.200 ± 0.984, 13.162 ± 0.486, 13.287 ± 0.787 and 13.500 ± 0.891 μm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP-induced hepatotoxicity.

  12. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    Abeer Hanafy; Aldawsari, Hibah M; Badr, Jihan M.; Amany K. Ibrahim; Seham El-Sayed Abdel-Hady

    2016-01-01

    The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophe...

  13. Hepatic Hemodynamics and Elevation of Liver Stiffness as Possible Predictive Markers of Late-onset Hepatic Failure.

    Science.gov (United States)

    Kakisaka, Keisuke; Kuroda, Hidekatsu; Abe, Tamami; Suzuki, Yuji; Yoshida, Yuichi; Kataoka, Kojiro; Miyamoto, Yasuhiro; Ishida, Kazuyuki; Takikawa, Yasuhiro

    2016-01-01

    A 52-year-old Japanese woman admitted to our hospital for the treatment of liver dysfunction due to an undetermined cause developed disorientation on the 58th hospital day and was diagnosed with late-onset liver failure. Abdominal ultrasound examinations were performed several times from the admission. Before the disorientation appeared, the results of the examinations revealed that the portal flow decreased, after which the hepatic arterial flow increased and the degree of liver stiffness became elevated. Although the pathophysiology of these changes remains unclear, hemodynamic changes and elevation of liver stiffness might be predictive markers of severe liver tissue damage.

  14. Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Yue-Ying He; Bao-Xu Zhang; Feng-Lan Jia

    2011-01-01

    AIM: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP)- induced hepatotoxicity in C57BL/6J mice. METHODS: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined. RESULTS: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously. CONCLUSION: BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism.

  15. Sirtuin 1 modulation in rat model of acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wojnarová, L; Kutinová Canová, N; Farghali, H; Kučera, T

    2015-01-01

    Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

  16. Protective Role of α2HS-Glycoprotein in HBV-Associated Liver Failure

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    Xue-Gong Fan

    2011-06-01

    Full Text Available n this study, levels of plasma α2-Heremans-Schmid glycoprotein, serum tumor necrosis factor-α, serum liver function parameters and short-term mortality were measured in 100 hepatitis B patients. Release of interleukin-6 and tumor necrosis factor-α from the lipopolysaccharide-stimulated peripheral blood mononuclear cells in the presence/absence of spermine and α2-Heremans-Schmid glycoprotein were analyzed by enzyme-linked immunosorbent assay to determine the significance and potential mechanism of α2-Heremans-Schmid glycoprotein in hepatitis B virus-associated liver damage. Results showed that serum α2-Heremans-Schmid glycoprotein levels in acute-on-chronic liver failure patients were significantly lower than that in chronic hepatitis B patients or healthy controls (p < 0.05. A negative dependence between serum human α2-Heremans-Schmid glycoprotein and tumor necrosis factor-α levels was observed. Interleukin-6 and tumor necrosis factor-α levels in the lipopolysaccharide-induced peripheral blood mononuclear cell supernates were significantly reduced by spermine and/or α2-Heremans-Schmid glycoprotein. The latter two proteins jointly inhibited cytokine release. These observations suggest that plasma α2-Heremans-Schmid glycoprotein is an independent marker of liver damage and a prognostic indicator of hepatitis B virus chronicity. It may reduce liver inflammation by partially inhibiting release of inflammatory factors from activated peripheral blood mononuclear cells.

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

    DEFF Research Database (Denmark)

    Laursen, Tea Lund; Sandahl, Thomas D; Støy, Sidsel;

    2015-01-01

    BACKGROUND & AIMS: 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. METHODS: Serum samples from 75 patients enrolled by the US ALF Study Group were collected on days 1 and 3. We...

  18. Successful Treatment of Corticosteroid with Antiviral Therapy for a Neonatal Liver Failure with Disseminated Herpes Simplex Virus Infection

    OpenAIRE

    Shinji Maeba; Shunji Hasegawa; Maiko Shimomura; Takuya Ichimura; Kazumasa Takahashi; Masashi Motoyama; Shinnosuke Fukunaga; Yoshinori Ito; Takashi Ichiyama; Shouichi Ohga

    2015-01-01

    Background - Herpes simplex virus (HSV) infection carries one of the poorest outcomes of neonatal liver failure (NLF). Neonates with disseminated HSV infection can develop hemophagocytic lymphohistiocytosis (HLH), and occasionally need orthotopic liver transplantation. Early interventions may be critical for the cure of NLF. Case Report - We describe herewith a 6-day-old neonate with fulminant hepatic failure due to disseminated HSV-1 infection, who successfully responded to high-dose cor...

  19. Acute Liver Failure in an Adult, a Rare Complication of Alagille Syndrome: Case Report and Brief Review.

    Science.gov (United States)

    Frongillo, F; Bianco, G; Silvestrini, N; Lirosi, M C; Sanchez, A M; Nure, E; Gaspari, R; Avolio, A W; Sganga, G; Agnes, S

    2015-09-01

    Alagille syndrome (AS) is an autosomal-dominant, multisystem disorder affecting the liver, heart, eyes, skeleton, and face. The manifestations are predominantly pediatric. Diagnosis is based on findings of a paucity of bile ducts on liver biopsy combined with ≥3 of 5 major clinical criteria. Orthotopic liver transplantation (OLT) is the only option for treating patients who developed liver failure, portal hypertension, severe itching, and xanthomatosis. It is difficult to establish clear criteria for OLT; indications are controversial because of the wide variety of clinical symptoms and the multisystem involvement. Generally, AS-associated liver disease is never an acute illness. We report the case of a 28-year-old woman with AS who underwent urgent OLT for acute liver failure. At 24 months posttransplant, the patient is in good clinical condition and with normal hepatic and renal function.

  20. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

  1. Prognostic Factors Predicting Poor Outcome in Living-Donor Liver Transplantation for Fulminant Hepatic Failure.

    Science.gov (United States)

    Kim, T-S; Kim, J M; Kwon, C H D; Kim, S J; Joh, J-W; Lee, S-K

    2017-06-01

    Living-donor liver transplantation (LDLT) has been accepted as feasible treatment for fulminant hepatic failure (FHF), although it has generated several debatable issues. In this study, we investigated the prognostic factors predicting fatal outcome after LDLT for FHF. From April 1999 to April 2011, 60 patients underwent LT for acute liver failure, including 42 patients for FHF at Samsung Medical Center, Seoul, Korea. Among 42 patients, 30 patients underwent LDLT for FHF, and the database of these patients was analyzed retrospectively to investigate the prognostic factors after LDLT for FHF. Among 30 patients, 7 patients (23%) died during the in-hospital period within 6 months, and 23 patients (77%) survived until recently. In univariate analyses, donor age (>35 years), graft volume (GV)/standard liver volume (SLV) (120 minutes), hepatic encephalopathy (grade IV), hepato-renal syndrome (HRS), and history of ventilator care were associated with fatal outcome after LDLT for FHF. In multivariate analyses, HRS, GV/SLV (35 years) were significantly associated with fatal outcome. Although the statistical significance was not shown in this analysis (P = .059), hepatic encephalopathy grade IV also appears to be a risk factor predicting fatal outcome. The survival of patients with FHF undergoing LDLT was comparable to that in published data. In this study, HRS, GV/SLV 35 years are the independent poor prognostic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Hyperlactatemia in patients with non-acetaminophen-related acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Pilar Taurá; Graciela Martinez-Palli; Julia Martinez-Ocon; Joan Beltran; Gerard Sanchez-Etayo; Jaume Balust; Teresa Anglada; Antoni Mas; Juan-Carlos Garcia-Valdecasas

    2006-01-01

    AIM: To characterize hyperlactatemia in patients with non-acetaminophen acute liver failure (ALF) in an attempt to clarify the mechanisms implicated and the role as a prognosis factor.METHODS: In the setting of liver transplantation, 63 consecutive patients with non-acetaminophen acute liver failure were studied in relation to tissue oxygenation,hemodynamic and metabolic parameters. Before and after transplantation, the number of infected patients and outcome were registered.RESULTS: Acute ALF showed higher levels of lactate than subacute ALF (5.4±1 mmol/L versus 2.2 ± 0.6 mmol/L, P=0.01). Oxygenation parameters were within the normal range. Lactate levels showed good correlation with respiratory quotient (r= 0.759, P< 0.005), mean glucose administration (r=0.664, P=0.01) and encephalopathy (r=0.698, P= 0.02), but not with splanchnic arteriovenous difference in PCO2, pH and the presence of infection (P=0.1). Portal vein lactate was higher (P< 0.05) than arterial and mixed venous lactate,suggesting its production of hyperlactatemia in the intestine and spleen. The presence of infection was an independent predictor of survival. CONCLUSION: Hyperlactatemia is not a prognosis factor due to byproduct of the overall acceleration in glycolysis.

  3. Cadaveric liver transplantation for non-acetaminophen fulminant hepatic failure: A 20-year experience

    Institute of Scientific and Technical Information of China (English)

    Olivier Detry; Jacques Bela(i)che; Michel Meurisse; Pierre Honor; Arnaud De Roover; Carla Coimbra; Jean Delwaide; Marie-France Hans; Marie Hélène Delbouille; Joseé Monard; Jean Joris; Pierre Damas

    2007-01-01

    AIM: To investigate the long-term results of liver transplantation (LT) for non-acetaminophen fulminant hepatic failure (FHF).METHODS: Over a 20-year period, 29 FHF patients underwent cadaveric whole LT. Most frequent causes of FHF were hepatitis B virus and drug-related (not acetaminophen) liver failure. All surviving patients were regularly controlled at the out-patient clinic and none was lost to follow-up. Mean follow-up was 101 mo.RESULTS: One month, one-, five- and ten-year patient survival was 79%, 72%, 68% and 68%, respectively.One month, one-, five- and ten-year graft survival was 69%, 65%, 51% and 38%, respectively. Six patients needed early (< 2 mo) retransplantation, four for primary non-function, one for early acute refractory rejection because of ABO blood group incompatibility,and one for a malignant tumor found in the donor.Two patients with hepatitis B FHF developed cerebral lesions peri-transplantion: One developed irreversible and extensive brain damage leading to death, and one suffered from deep deficits leading to continuous medical care in a specialized institution.CONCLUSION: Long-term outcome of patients transplanted for non-acetaminophen FHF may be excellent. As the quality of life of these patients is also particularly good, LT for FHF is clearly justified, despite lower graft survival compared with LT for other liver diseases.

  4. Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice.

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    Lu, Yihong; Sun, Jinchun; Petrova, Katya; Yang, Xi; Greenhaw, James; Salminen, William F; Beger, Richard D; Schnackenberg, Laura K

    2013-12-01

    Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds.

  5. Evaluation of nephroprotective, diuretic, and antioxidant activities of plectranthus amboinicus on acetaminophen-induced nephrotoxic rats.

    Science.gov (United States)

    Palani, S; Raja, S; Naresh, R; Kumar, B Senthil

    2010-05-01

    Plectranthus amboinicus (PA), commonly known as country borage, is a folkoric medicinal plant. Juice from its leaves is commonly used for illnesses including liver and renal conditions in the Asian sub-continent. Acetaminophen (APAP), used as an analgesic, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective, diuretic, and antioxidant activities of the ethanol extract of PA at two doses of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. This study shows that APAP significantly increases the levels of serum urea (UR), hemoglobin (Hb), total leukocyte count, creatinine, raised body weight, and reduced levels of neutrophils, granulocytes, uric acid, and platelet concentration. Ethanol extract of PA rescued these phenotypes by increasing anti-oxidative responses as assessed by biochemistry and histopathology. In addition, the ethanol extract of PA at two doses showed a significant diuretic activity by increased levels of total urine output and urinary elerolytes such as sodium and potassium. In conclusion, these data suggest that the ethanol extract of PA possess nephroprotective and antioxidant effects against APAP-induced nephrotoxicity and strong diuretics effect in rats.

  6. Antioxidant and Hepatoprotective Efficiency of Selenium Nanoparticles Against Acetaminophen-Induced Hepatic Damage.

    Science.gov (United States)

    Amin, Kamal Adel; Hashem, Khalid Shaban; Alshehri, Fawziah Saleh; Awad, Said T; Hassan, Mohammed S

    2017-01-01

    Overdoses of acetaminophen (APAP), a famous and widely used drug, may have hepatotoxic effects. Nanoscience is a novel scientific discipline that provides specific tools for medical science problems including using nano trace elements in hepatic diseases. Our study aimed to assess the hepatoprotective role of selenium nanoparticles (Nano-Se) against APAP-induced hepatic injury. Twenty-four male rats were classified into three equal groups: a control group that received 0.9 % NaCl, an APAP-treated group (oral administration), and a group treated with Nano-Se (10-20 nm, intraperitoneal (i.p.) injection) and APAP (oral administration). APAP overdose induced significant elevations in liver function biomarkers, hepatic lipid peroxidation, hepatic catalase, and superoxide dismutase (SOD), decreased the reduced glutathione (GSH) content and glutathione reductase (GR) activity, and stimulated significant DNA damage in hepatocytes, compared to control rats. Nano-Se administration improved the hepatic antioxidant protection mechanism and decreased cellular sensitivity to DNA fragmentation. Nano-Se exhibits a protective effect against APAP-induced hepatotoxicity through improved liver function and oxidative stress mediated by catalase, SOD, and GSH and decreases hepatic DNA fragmentation, a hepatic biomarker of cell death. Nano-Se could be a novel hepatoprotective strategy to inhibit oxidative stress.

  7. Propolis reverses acetaminophen induced acute hepatorenal alterations: a biochemical and histopathological approach.

    Science.gov (United States)

    Nirala, Satendra Kumar; Bhadauria, Monika

    2008-04-01

    The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it.

  8. Risk factors for antibiotic prophylaxis failure in patients with liver cirrhosis and upper gastrointestinal bleeding

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    LI Xiaolou

    2016-02-01

    Full Text Available ObjectiveTo investigate the risk factors for antibiotic prophylaxis failure in patients with liver cirrhosis and upper gastrointestinal bleeding. MethodsEighty-two patients with liver cirrhosis and upper gastrointestinal bleeding who were admitted to our hospital from January 2011 to June 2014 were analyzed retrospectively. All patients received third-generation cephalosporins as the antibiotic prophylaxis for 7 days. The therapeutic effect of prophylaxis within two weeks was analyzed, and the clinical features were compared between prophylaxis response group and non-response group. The t-test or Mann-Whitney U test was applied for comparison of continuous data between groups, the chi-square test was applied for comparison of categorical data between groups, and the logistic regression analysis was applied to determine the risk factors for antibiotic prophylaxis failure. ResultsA total of 38 patients (46.4% developed secondary infection. There were significant differences in prothrombin time, proportion of patients admitted to the intensive care unit (ICU, duration of ICU stay, proportion of patients who received deep venipuncture, Child-Pugh classification, and Child-Pugh score between the prophylaxis response group and non-response group (P<0.05. Child-Pugh classification (OR=2.455, 95%CI: 1.01-5.97, P=0.048 and admission to the ICU (OR=4.12, 95%CI: 1.32-12.83, P=0.015 were the independent risk factors for antibiotic prophylaxis failure. ConclusionAntibiotic prophylaxis with third-generation cephalosporins has a high failure rate, and admission to the ICU and a high Child-Pugh classification are the independent risk factors for antibiotic prophylaxis failure.

  9. [Therapeutic effect of the latest extracorporal elimination procedure (Prometheus treatment) in acute liver failure caused by intoxication].

    Science.gov (United States)

    Bakos, Agnes; Rikker, Csaba; Tóvárosi, Szilveszter; Kárteszi, Mihály

    2007-10-21

    Despite intensive therapy the mortality of acute liver failure without organ transplantation is 60-90%. Because of organ shortage in liver transplantation, a significant number of patients dies while being on the waiting list. In order to diminish the mortality, various trials were introduced to remove the albumin-bound and water-soluble toxins in liver failure with the aim to support the spontaneous regeneration of the liver and maintaining the patients alive until liver transplantation. Prometheus treatment is a relatively new technique combining Fractionated Plasma Separation and Adsorption (FPSA) with a high-flux dialysis. During the procedure the patient's own separated albumin-rich plasma passes through special adsorbents making possible the elimination of albumin-bound toxins, while hemodialysis gets rid of water-soluble toxins. The authors' intention was to demonstrate the efficiency of Prometheus treatment in acute liver failure caused by intoxication. Prometheus treatment was indicated in three patients who suffered from severe intoxication with paracetamol, potassium permanganate and Amanita phalloides, which resulted in a hepatic failure incurable with conservative therapy. Ten treatments were performed in the three female patients. No serious complication was observed. Due to the treatment the albumin-bound (indirect bilirubin p = 0.048; bile acid p = 0.001) and water-soluble (direct bilirubin p = 0.002; creatinine p = 0.007) toxins were significantly decreased. The level of ammonia, urea nitrogen, fibrinogen and antithrombin III did not change significantly. All the three patients were cured without liver transplantation. Prometheus treatment removes efficiently the accumulating toxins in acute liver failure. It is a safe elimination technique. In cases untreatable with conservative therapy it makes possible maintaining the patients alive until the liver regenerates spontaneously, or liver transplantation is feasible.

  10. Economic evaluation of the artificial liver support system MARS in patients with acute-on-chronic liver failure

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    Hessel Franz P

    2006-10-01

    Full Text Available Abstract Background Acute-on-chronic liver failure (ACLF is a life threatening acute decompensation of a pre-existing chronic liver disease. The artificial liver support system MARS is a new emerging therapeutic option possible to be implemented in routine care of these patients. The medical efficacy of MARS has been demonstrated in first clinical studies, but economic aspects have so far not been investigated. Objective of this study was to estimate the cost-effectiveness of MARS. Methods In a clinical cohort trial with a prospective follow-up of 3 years 33 ACLF-patients treated with MARS were compared to 46 controls. Survival, health-related quality of life as well as direct medical costs for in- and outpatient treatment from a health care system perspective were determined. Based on the differences in outcome and indirect costs the cost-effectiveness of MARS expressed as incremental costs per life year gained and incremental costs per QALY gained was estimated. Results The average initial intervention costs for MARS were 14600 EUR per patient treated. Direct medical costs over 3 years follow up were overall 40000 EUR per patient treated with MARS respectively 12700 EUR in controls. The 3 year survival rate after MARS was 52% compared to 17% in controls. Kaplan-Meier analysis of cumulated survival probability showed a highly significant difference in favour of MARS. Incremental costs per life-year gained were 31400 EUR; incremental costs per QALY gained were 47200 EUR. Conclusion The results after 3 years follow-up of the first economic evaluation study of MARS based on empirical patient data are presented. Although high initial treatment costs for MARS occur the significantly better survival seen in this study led to reasonable costs per live year gained. Further randomized controlled trials investigating the medical efficacy and the cost-effectiveness are recommended.

  11. Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure.

    Science.gov (United States)

    Nakazawa, Atsuko; Nakano, Natsuko; Fukuda, Akinari; Sakamoto, Seisuke; Imadome, Ken-Ichi; Kudo, Toyoichiro; Matsuoka, Kentaro; Kasahara, Mureo

    2015-03-01

    The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV-induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV-encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF.

  12. Quantitative multivoxel {sup 1}H MR spectroscopy of the brain in children with acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Sijens, Paul E.; Alkefaji, Heyder; Meiners, Linda C.; Oudkerk, Matthijs [University Medical Center Groningen and University of Groningen, Department of Radiology, Beatrix Children' s Hospital, Groningen (Netherlands); Lunsing, Roelineke J. [University Medical Center Groningen and University of Groningen, Department of Child Neurology, Beatrix Children' s Hospital, Groningen (Netherlands); Spronsen, Francjan J. van; Verkade, Henkjan J. [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Beatrix Children' s Hospital, Groningen (Netherlands)

    2008-11-15

    Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P < 0.01; lactate + 33%, P < 0.05) and higher Glx in grey matter (Glx + 125%: P < 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P < 0.05), and negative correlations between grey or white matter Glx and venous pH (P < 0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, {gamma}-glutamyl transpeptidase, alkaline phosphatase). (orig.)

  13. Mars and Prometheus: our clinical experience in acute chronic liver failure.

    Science.gov (United States)

    Faenza, S; Baraldi, O; Bernardi, M; Bolondi, L; Coli, L; Cucchetti, A; Donati, G; Gozzetti, F; Lauro, A; Mancini, E; Pinna, A D; Piscaglia, F; Rasciti, L; Ravaioli, M; Ruggeri, G; Santoro, A; Stefoni, S

    2008-05-01

    In our clinical context, there are two groups that practice blood purification treatments on acute or chronic liver failure (AoCLF) patients: one group used MARS (molecular adsorbent recirculating system) and the other Prometheus. The MARS group used the lack of response to standard medical treatment after 72 hours of observation as the access criterion. The Prometheus group used the access criteria of the multicenter Helios protocol for patients in AoCLF, as well as those with primary nonfunction (PNF) and secondary liver insufficiency. Both groups performed treatment sessions of at least 6 hours, which were repeated at least every 24 to 36 hours. The 56 treated AoCLF patients underwent 278 treatment sessions; 41 out of 191 procedures with MARS and 16 out of 87 procedures with prometheus, which was also applied in two cases in PNF and four in secondary liver insufficiency. The results showed that both systems accomplished a good purification efficiency and that application to patients enabled reinstatement on the transplant list and grafts in 70% of the cases with either method. Treatment led to recovery in dysfunction among patients not destined for transplantation, achieved with a 48.5% 3-month survival in the MARS group and 33.5% in the Prometheus groups. The treatment results were inversely proportional to the MELD at the time of entry; The treatment appeared to be pointless. Among PNF and secondary liver insufficiency cases.

  14. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

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    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

  15. A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.

    Science.gov (United States)

    Tamai, Satoshi; Iguchi, Takuma; Niino, Noriyo; Mikamoto, Kei; Sakurai, Ken; Sayama, Ayako; Shimoda, Hitomi; Takasaki, Wataru; Mori, Kazuhiko

    2017-01-01

    Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

  16. Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.

    Science.gov (United States)

    Tran, A; Tréluyer, J M; Rey, E; Barbet, J; Ferracci, G; d'Athis, P; Vincent, J; Pons, G

    2001-02-01

    Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

  17. Therapeutic potential of alpha-ketoglutarate against acetaminophen-induced hepatotoxicity in rats

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    Lalita Mehra

    2016-01-01

    Full Text Available Objective: Alpha-ketoglutarate (α-KG is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control: Normal Saline, Group II (APAP: A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG: APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and alkaline phosphatase (ALP with oxidative stress markers including malondialdehyde (MDA, reduced glutathione (GSH, superoxide dismutase (SOD, catalase (CAT, and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05 reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats.

  18. [Infusion-associated kidney and liver failure in undiagnosed hereditary fructose intolerance].

    Science.gov (United States)

    Müller-Wiefel, D E; Steinmann, B; Holm-Hadulla, M; Wille, L; Schärer, K; Gitzelmann, R

    1983-06-24

    Appendectomy was performed in a 14 1/2-year-old boy with undiagnosed hereditary fructose intolerance because of chronic recurrent abdominal pain. During and after operation fructose containing solutions were infused. The patient received a total of 250 g fructose intravenously over 30 hours. Hours after onset of infusion he became soporous, hypoglycaemic and acidotic and was anuric after one day. Although the diagnosis was suspected by the end of the first postoperative day and fructose had been cancelled and haemodialysis been started, the boy died after a further 3 days with signs of acute kidney and liver failure. The diagnosis of hereditary fructose intolerance was biochemically established in post mortem liver tissue. This case recalls the fact that fructose, sorbitol or invert sugars should not be added to infusion solutions as they may be toxic for healthy persons and imply a lethal risk for patients with undiagnosed hereditary fructose intolerance, even well beyond the baby and infant period.

  19. The effect of Prometheus device on laboratory markers of inflammation and tissue regeneration in acute liver failure management.

    Science.gov (United States)

    Rocen, M; Kieslichova, E; Merta, D; Uchytilova, E; Pavlova, Y; Cap, J; Trunecka, P

    2010-11-01

    Prometheus, based on modified fractionated plasma separation and adsorption (FPSA) method, is used in the therapy of acute liver failure as a bridge to liver transplantation. As the therapeutic effect of Prometheus is caused not only by the elimination of terminal metabolites, the aim of the study was to identify the effect of FPSA on the levels of cytokines and markers of inflammation and liver regeneration. Previous studies assessing cytokine levels involved mostly acute-on-chronic liver failure patients. Data concerning markers of inflammation and liver regeneration are not published yet. Eleven patients (three males, eight females) with acute liver failure were investigated. These patients underwent 37 therapeutic sessions on Prometheus device. Before and after each treatment, the plasma levels of selected cytokines, tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), procalcitonin (PCT), hepatocyte growth factor (HGF), and α(1) fetoprotein, were measured, and the kinetics of their plasma concentrations was evaluated. Before the therapy, elevated levels of interleukin (IL)-6, IL-8, IL-10, TNFα, CRP, and PCT were detected. The level of TNFα, CRP, PCT, and α(1) fetoprotein decreased significantly during the therapy. In contrast, an increase of HGF was detected. The decline of IL-6, IL-8, and IL-10 concentrations was not significant. Our results show that Prometheus is highly effective in clearing inflammatory mediators responsible for systemic inflammatory response syndrome and affects the serum levels of inflammatory and regeneration markers important for management of acute liver failure.

  20. Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.

    Directory of Open Access Journals (Sweden)

    Jody A Rule

    Full Text Available Because acute liver failure (ALF patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD subjects served as controls.Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169. PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001. Subjects with acetaminophen (APAP toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.

  1. Liver disease and the e antigen in HBsAg carriers with chronic renal failure.

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    Coughlin, G P; Van Deth, A G; Disney, A P; Hay, J; Wangel, A G

    1980-01-01

    This study was undertaken to assess the frequency of development and the stages of evolution of chronic liver disease in patients with renal failure who are chronic carriers of hepatitis B surface antigen. Cirrhosis or chronic active hepatitis developed in five of 21 patients and could not be predicted by the initial histological appearance or by HLA-A and B typing but was associated with the e antigen in four of the five patients. However, the antigen was not a consistent indicator of a poor...

  2. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity.

    Science.gov (United States)

    Jin, Fen; Wan, Chunpeng; Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity.

  3. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity

    Science.gov (United States)

    Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity. PMID:28234915

  4. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

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    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Abiko, Yumi [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Yamada, Hidenori [Jobu Hospital for Respiratory Diseases, Maebashi 371-0048 (Japan); Akahoshi, Noriyuki [Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543 (Japan); Kasahara, Tadashi [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Kumagai, Yoshito [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Ishii, Isao, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan)

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/−}, and

  5. Protective Effect of Sundarban Honey against Acetaminophen-Induced Acute Hepatonephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Rizwana Afroz

    2014-01-01

    Full Text Available Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP- induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg for 4 weeks, followed by the induction of hepatotoxicity and nephrotoxicity via the oral administration of a single dose of APAP (2 g/kg. Organ damage was confirmed by measuring the elevation of serum alkaline phosphatase (ALP, alanine transaminase (ALT, aspartate transaminase (AST, total protein (TP, total bilirubin (TB, urea, creatinine, and malondialdehyde (MDA. Histopathological alterations observed in the livers and the kidneys further confirmed oxidative damage to these tissues. Animals pretreated with Sundarban honey showed significantly markedly reduced levels of all of the investigated parameters. In addition, Sundarban honey ameliorated the altered hepatic and renal morphology in APAP-treated rats. Overall, our findings indicate that Sundarban honey protects against APAP-induced acute hepatic and renal damage, which could be attributed to the honey’s antioxidant properties.

  6. Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen-induced toxicity in humans.

    Science.gov (United States)

    Thiel, C; Cordes, H; Baier, V; Blank, L M; Kuepfer, L

    2017-02-01

    Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP-induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  7. Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Alanazi, Abdulrazaq; Algfeley, Saleh G; Al-Hosaini, Khaled A; Korashy, Hesham M; Imam, Faisal; Nagi, Mahmoud N

    2017-04-01

    Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS. © 2016 Wiley Periodicals, Inc.

  8. Reversal of acetaminophen induced subchronic hepatorenal injury by propolis extract in rats.

    Science.gov (United States)

    Bhadauria, Monika; Nirala, Satendra Kumar

    2009-01-01

    The ethanolic extract of propolis (200mg/kg, p.o.) was evaluated against acetaminophen (APAP; 20mg/kg, p.o.) induced subchronic hepatorenal injury in rats. Administration of APAP significantly increased the release of serum transaminases, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transpeptidase, bilirubin and serum proteins, whereas concomitantly decreased hemoglobin, blood sugar and albumin. Hepatorenal reduced glutathione and activities of superoxide dismutase and catalase, hepatic CYPs i.e., aniline hydroxylase and amidopyrine-N-demethylase were significantly decreased after APAP intoxication. Lipid peroxidation showed significant elevation in both organs significantly after APAP assault. Total proteins, glycogen contents and the activities of certain metabolic enzymes i.e., adenosine triphosphatase, alkaline phosphatase and acid phosphatase were altered after APAP administration. Propolis extract exhibited curative effects by reversing APAP induced alterations in blood biochemical variables, CYP enzymes and markers of oxidative stress. Histopathological analysis of liver and kidney was consistent with the biochemical findings and led us to conclude the curative potential of propolis against APAP induced hepatorenal injury. Copyright © 2008 Elsevier B.V. All rights reserved.

  9. Extracorporeal Membrane Oxygenation Can Save Lives in Children With Heart or Lung Failure After Liver Transplantation.

    Science.gov (United States)

    Jean, Sandrine; Chardot, Christophe; Oualha, Mehdi; Capito, Carmen; Bustarret, Olivier; Pouard, Philippe; Renolleau, Sylvain; Lacaille, Florence; Dupic, Laurent

    2017-09-01

    The risk of cardiac or lung failure after liver transplantation (LT) is significant. In rare cases, the usual intensive care techniques fail to maintain organ oxygenation with a risk of multiorgan dysfunction. Although extracorporeal membrane oxygenation (ECMO) is a difficult and risky procedure, it can be proposed as life-saving. Four children with either acute pulmonary (three) or cardiac (one) failure after LT, and the criteria that decided the use of ECMO (level of ventilation and results, dosage of inotropic drugs, cardiac ultrasound, blood lactate) were retrospectively reported. These patients, 1-11 years old, were treated with either veno-arterial (three) or veno-venous (one) ECMO. Two experienced a full recovery, with 3 and 6 years of follow-up. Two died of systemic inflammatory response syndrome (SIRS) due to ECMO, and relapse of heart failure due to the underlying disease. Although our patients' survival was only 50%, we showed that ECMO can be useful in children after LT. It should be considered before the development of irreversible multiorgan failure. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  10. Resistance to acetaminophen-induced hepatotoxicity in glutathione S-transferase Mu 1-null mice.

    Science.gov (United States)

    Arakawa, Shingo; Maejima, Takanori; Fujimoto, Kazunori; Yamaguchi, Takashi; Yagi, Masae; Sugiura, Tomomi; Atsumi, Ryo; Yamazoe, Yasushi

    2012-01-01

    We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3β and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity.

  11. Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G.

    Science.gov (United States)

    Abdelaziz, Heba A; Shaker, Mohamed E; Hamed, Mohamed F; Gameil, Nariman M

    2017-06-05

    The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Association between plasma fibrinogen levels and mortality in acute-on-chronic hepatitis B liver failure.

    Science.gov (United States)

    Shao, Zhexin; Zhao, Ying; Feng, Limin; Feng, Guofang; Zhang, Juanwen; Zhang, Jie

    2015-01-01

    Acute-on-chronic liver failure (AoCLF) is the most common type of liver failure and is associated with high mortality. Fibrinogen is critical in maintaining primary and secondary hemostasis. Therefore, we prospectively analyzed the association between fibrinogen and outcomes in AoCLF patients. Plasma fibrinogen was measured in 169 AoCLF, 173 chronic hepatitis B (CHB), and 171 healthy patients using a coagulation method. The predictive ability of fibrinogen for 3-month mortality in AoCLF patients was assessed using receiver operating characteristic (ROC) curve and multivariable logistic regression analyses. Plasma fibrinogen was significantly lower in nonsurvivor AoCLF patients compared with survivor AoCLF, CHB, and control patients. The sensitivity, specificity, and area under the ROC curve of 1/fibrinogen predicting mortality in AoCLF patients were 66.7%, 72.5%, and 0.746 (95% confidence interval (CI): 0.672-0.820, P fibrinogen cutoff value was 0.90 g/L. On multivariate logistic regression analysis, low fibrinogen was an independent factor predicting mortality (odds ratio: 0.304; 95% CI: 0.094-0.983; P = 0.047). Nonsurvivor AoCLF patients had significantly decreased fibrinogen levels, suggesting that low plasma fibrinogen may be a useful predictor of poor prognosis in AoCLF patients.

  13. The frequency and determinants of liver stiffness measurement failure: a retrospective study of "real-life" 38,464 examinations.

    Directory of Open Access Journals (Sweden)

    Dong Ji

    Full Text Available To investigate the frequency and determinants of liver stiffness measurement (LSM failure by means of FibroScan in "real-life" Chinese patients.A total of 38,464 "real-life" Chinese patients in 302 military hospital of China through the whole year of 2013, including asymptomatic carrier, chronic hepatitis B, chronic hepatitis C, liver cirrhosis (LC, alcoholic liver disease, autoimmune liver disease, hepatocellular carcinoma (HCC and other, were enrolled, their clinical and biological parameters were retrospectively investigated. Liver fibrosis was evaluated by FibroScan detection. S probe (for children with height less than 1.20 m and M probe (for adults were used. LSM failure defined as zero valid shots (unsuccessful LSM, or the ratio of the interquartile range to the median of 10 measurements (IQR/M greater than 0.30 plus median LSM greater or equal to 7.1 kPa (unreliable LSM.LSM failure occurred in 3.34% of all examinations (1286 patients out of 38,464, among them, there were 958 cases (2.49% with unsuccessful LSM, and 328 patients (0.85% with unreliable LSM. Statistical analyses showed that LSM failure was independently associated with body mass index (BMI greater than 30 kg/m(2, female sex, age greater than 50 years, intercostal spaces (IS less than 9 mm, decompensated liver cirrhosis and HCC patients. There were no significant differences among other diseases. By changing another skilled operator, success was achieved on 301 cases out of 1286, which reduced the failure rate to 2.56%, the decrease was significant (P<0.0001.The principal reasons of LSM failure are ascites, obesity and narrow of IS. The failure rates of HCC, decompensated LC, elder or female patients are higher. These results emphasize the need for adequate operator training, technological improvements and optimal criteria for specific patient subpopulations.

  14. Establishment of a Novel Simplified Surgical Model of Acute Liver Failure in the Cynomolgus Monkey

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    Lei Cai

    2016-01-01

    Full Text Available Models using large animals that are suitable for studying artificial liver support system (ALSS are urgently needed. Presently available acute liver failure (ALF models mainly involve pigs or dogs. Establishment of current surgical ALF models (hepatectomy/devascularization requires either very good surgical skills or multistep processes—even multiple stages of surgery. Therefore, it is necessary to develop a simplified surgical method. Here we report a novel simplified surgical ALF model using cynomolgus monkeys. Six monkeys underwent portal-right renal venous shunt combined with common bile duct ligation and transection (PRRS + CBDLT. Postoperatively, the monkeys had progressively increased listlessness, loss of appetite, and obvious jaundice. Blood biochemistry levels (Amm, ALT, AST, TBiL, DBiL, ALP, LDH, CK, and Cr and prothrombin time (PT were significantly increased (all P<0.01 and albumin (ALB was markedly reduced (P<0.01 compared with baseline values. Histological examination of liver specimens on postoperative day 10 revealed cholestasis and inflammation. PRRS + CBDLT produced ALF that closely correlated with clinical situations. Compared with other surgical or drug ALF models, ours was simplified and animals were hemodynamically stable. This model could provide a good platform for further research on ALSS, especially regarding their detoxification functions.

  15. Etiologies and Outcomes of Acute Liver Failure in a Spanish Community

    Directory of Open Access Journals (Sweden)

    Emilio Fábrega

    2013-01-01

    Full Text Available Previous retrospective study (1992 to 2000 performed in Spain showed that drug toxicity, viral hepatitis, and indeterminate etiology were the most prevalent causes of acute liver failure (ALF. In the last decade, there is no information about ALF in our country. For these reasons we analyze retrospectively, in a ten-year period (2000 to 2010, the presumed causes, clinical characteristics, course, and outcome of ALF in a Spanish community. Causes of ALF were indeterminate in 4 patients (24%, acute hepatitis B infection in 4 patients (24%, drug or toxic reactions in 4 patients (24%, including one case of acetaminophen overdose, followed by miscellaneous causes. The overall short-term survival (6 weeks after admission was 65%. Liver transplantation was performed in 11 patients with a survival of 82%. Despite fulfilling criteria, 2 patients were not transplanted because of contraindications; they both died. In summary, acute hepatitis B and indeterminate cause are still being the most frequent causes of ALF in our region, and patients with ALF have an excellent chance of survival after emergency liver transplantation. Acetaminophen overdose still represents a very rare cause of ALF in our community.

  16. Plasma Adiponectin Levels in Acute Liver Failure Patients Treated with Plasma Filtration with Dialysis and Plasma Exchange.

    Science.gov (United States)

    Yamamoto, Hiroshi; Nakae, Hajime; Uji, Yoshitaka; Maeda, Kazuhisa; Tani, Tohru; Eguchi, Yutaka

    2015-08-01

    Plasma filtration with dialysis (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside of the hollow fibers. Improvement of hypoadiponectinemia is considered to be a useful therapeutic approach for ameliorating fatal conditions including cardio-metabolic and infectious disease. We investigated the effects of PDF in comparison to PE in terms of plasma adiponectin (APN) changes in patients with acute liver failure. Seventeen patients with liver failure were studied; PDF was performed 55 times and PE 14 times. Plasma APN levels increased significantly after PDF, while decreasing significantly after PE. PDF appears to be among the most useful blood purification therapies in acute liver failure cases in terms of increasing APN levels.

  17. Intraportal mesenchymal stem cell transplantation prevents acute liver failure through promoting cell proliferation and inhibiting apoptosis

    Institute of Scientific and Technical Information of China (English)

    Jian-Feng Sang; Xiao-Lei Shi; Bin Han; Tao Huang; Xu Huang; Hao-Zhen Ren; Yi-Tao Ding

    2016-01-01

    BACKGROUND: Transplantation of mesenchymal stem cells (MSCs) has been regarded as a potential treatment for acute liver failure (ALF), but the optimal route was unknown. The present study aimed to explore the most effective MSCs trans-plantation route in a swine ALF model. METHODS: The swine ALF model induced by intravenous injection of D-Gal was treated by the transplantation of swine MSCs through four routes including intraportal injection (InP group), hepatic intra-arterial injection (AH group), pe-ripheral intravenous injection (PV group) and intrahepatic injection (IH group). The living conditions and survival time were recorded. Blood samples before and after MSCs trans-plantation were collected for the analysis of hepatic function. The histology of liver injury was interpreted and scored in terminal samples. Hepatic apoptosis was detected by TUNEL assay. Apoptosis and proliferation related protein expressions including cleaved caspase-3, survivin, AKT, phospho-AKT (Ser473), ERK and phospho-ERK (Tyr204) were analyzed by Western blotting. RESULTS: The average survival time of each group was 10.7 ± 1.6 days (InP), 6.0±0.9 days (AH), 4.7±1.4 days (PV), 4.3± 0.8 days (IH), respectively, when compared with the average survival time of 3.8±0.8 days in the D-Gal group. The sur-vival rates between the InP group and D-Gal group revealed a statistically signiifcant difference (P CONCLUSIONS: Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC trans-plantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.

  18. Emerging role of liver X receptors in cardiac pathophysiology and heart failure.

    Science.gov (United States)

    Cannon, Megan V; van Gilst, Wiek H; de Boer, Rudolf A

    2016-01-01

    Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.

  19. Model for end-stage liver disease predicts right ventricular failure in patients with left ventricular assist devices.

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    Yost, Gardner L; Coyle, Laura; Bhat, Geetha; Tatooles, Antone J

    2016-03-01

    High rates of right ventricular failure continue to affect postoperative outcomes in patients implanted with left ventricular assist devices (LVADs). Development of right ventricular failure and implantation with right ventricular assist devices is known to be associated with significantly increased mortality. The model for end-stage liver disease (MELD) score is an effective means of evaluating liver dysfunction. We investigated the prognostic utility of postoperative MELD on post-LVAD implantation outcomes. MELD scores, demographic data, and outcomes including length of stay, survival, and postoperative right ventricular failure were collected for 256 patients implanted with continuous flow LVADs. Regression and Kaplan-Meier analyses were used to investigate the relationship between MELD and all outcomes. Increased MELD score was found to be an independent predictor of both right heart failure and necessity for RVAD implantation (OR 1.097, CI 1.040-1.158, p = 0.001; OR 1.121, CI 1.015, p = 0.024, respectively). Patients with RV failure and who underwent RVAD implantation had reduced postoperative survival compared to patients with RV dysfunction (no RV failure = 651.4 ± 609.8 days, RV failure = 392.6 ± 444.8 days, RVAD = 89.3 ± 72.8 days; p right heart failure and the necessity for RVAD implantation. Those patients with RV failure and RVADs experience significantly increased postoperative mortality compared to those without RV dysfunction.

  20. Living-related liver transplantation for fulminant hepatic failure in children.

    Science.gov (United States)

    Tanaka, K; Uemoto, S; Inomata, Y; Tokunaga, Y; Ueda, M; Tokka, A; Sato, B; Yamaoka, Y

    1994-01-01

    Liver transplantation is increasingly accepted as a choice of treatment for fulminant hepatic failure (FHF) since it has been proved to significantly improve the survival rate in these patients compared with other therapeutic modalities. We have successfully performed a total of 76 living related liver transplantations (LRLT) three of which were for FHF. The first case was an 11-year-old boy with FHF due to an unidentified cause. He had required plasmapheresis a total of 24 times and haemofiltration to save his life before LRLT. He was transplanted with a left lobe (420 g) graft, calculated as 1.05% of his weight (40 kg). He recovered hepatic function uneventfully and was discharged from hospital after 7 weeks. The second case was a 13-year-old girl who developed FHF with grade III encephalopathy due to acute Wilson's disease, and was referred to us. She underwent LRLT with a left lobe graft (440 g), estimated as 0.95% of her weight (47 kg), which functioned well after surgery. The third case was a 13-year-old girl with grade II encephalopathy due to acute Wilson's disease. She was 27% obese with a body weight of 58 kg. She underwent LRLT with ABO blood group incompatibility with a left lobe (352 g), estimated as 0.80% of her weight (modified 44 kg). She was discharged with sensorimotor neuropathy due to vitamin B deficiency. The present results suggest that LRLT is feasible for FHF both clinically and ethically, and that a partial liver graft weighing around 1% of the recipient's weight can maintain the recipient's life. We limit the diagnostic indication for LRLT to chronic liver disease, since an urgent situation may affect a voluntary decision for the patient's parents to donate the partial liver. However, LRLT is thought to be an acceptable choice of treatment provided it is requested by the patient and family. Furthermore, it is a potential option for resolving the graft shortage in paediatric liver transplantation, being independent of cadaver donor

  1. Renal Dysfunction Is an Independent Risk Factor for Mortality after Liver Resection and the Main Determinant of Outcome in Posthepatectomy Liver Failure

    Directory of Open Access Journals (Sweden)

    M. G. Wiggans

    2013-01-01

    Full Text Available Introduction. The aim of this study was to assess the interaction of liver and renal dysfunction as risk factors for mortality after liver resection. Materials and Methods. A retrospective analysis of 501 patients undergoing liver resection in a single unit was undertaken. Posthepatectomy liver failure (PHLF was defined according to the International Study Group of Liver Surgery (ISGLS definition (assessed on day 5 and renal dysfunction according to RIFLE criteria. 90-day mortality was recorded. Results. Twenty-three patients died within 90 days of surgery (4.6%. The lowest mortality occurred in patients without evidence of PHLF or renal dysfunction (2.7%. The mortality rate in patients with isolated PHLF or renal dysfunction was 20% compared to 45% in patients with both. Diabetes (, renal dysfunction (, and PHLF on day 5 ( were independent predictors of 90-day mortality. Discussion. PHLF and postoperative renal dysfunction are independent predictors of 90-day mortality following liver resection but the predictive value for mortality is significantly higher when failure of both organ systems occurs simultaneously.

  2. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism

    OpenAIRE

    Valencia, C. Alexander; Wang, Xinjian; Wang, Jin; Peters, Anna; Simmons, Julia R.; Moran, Molly C.; Mathur, Abhinav; Husami, Ammar; Qian, Yaping; Sheridan, Rachel; Bove, Kevin E.; Witte, David; Huang, Taosheng; Miethke, Alexander G.

    2016-01-01

    Background & Aims The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. Methods Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver sampl...

  3. Technical Failure of MR Elastography Examinations of the Liver: Experience from a Large Single-Center Study.

    Science.gov (United States)

    Wagner, Mathilde; Corcuera-Solano, Idoia; Lo, Grace; Esses, Steven; Liao, Joseph; Besa, Cecilia; Chen, Nelson; Abraham, Ginu; Fung, Maggie; Babb, James S; Ehman, Richard L; Taouli, Bachir

    2017-01-03

    Purpose To assess the determinants of technical failure of magnetic resonance (MR) elastography of the liver in a large single-center study. Materials and Methods This retrospective study was approved by the institutional review board. Seven hundred eighty-one MR elastography examinations performed in 691 consecutive patients (mean age, 58 years; male patients, 434 [62.8%]) in a single center between June 2013 and August 2014 were retrospectively evaluated. MR elastography was performed at 3.0 T (n = 443) or 1.5 T (n = 338) by using a gradient-recalled-echo pulse sequence. MR elastography and anatomic image analysis were performed by two observers. Additional observers measured liver T2* and fat fraction. Technical failure was defined as no pixel value with a confidence index higher than 95% and/or no apparent shear waves imaged. Logistic regression analysis was performed to assess potential predictive factors of technical failure of MR elastography. Results The technical failure rate of MR elastography at 1.5 T was 3.5% (12 of 338), while it was higher, 15.3% (68 of 443), at 3.0 T. On the basis of univariate analysis, body mass index, liver iron deposition, massive ascites, use of 3.0 T, presence of cirrhosis, and alcoholic liver disease were all significantly associated with failure of MR elastography (P technical failure rate of MR elastography with a gradient-recalled-echo pulse sequence was low at 1.5 T but substantially higher at 3.0 T. Massive ascites, iron deposition, and high body mass index were additional independent factors associated with failure of MR elastography of the liver with a two-dimensional gradient-recalled-echo pulse sequence. (©) RSNA, 2017.

  4. Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Hauerberg, John; Jørgensen, Linda;

    2010-01-01

    The pathogenesis of cerebral edema in acute liver failure is suggested, in in vitro and animal studies, to involve a compromised oxidative metabolism with a decrease in cerebral ATP levels and an increase in purine concentrations. In this study we hypothesize that the cerebral concentrations...... of hypoxanthine, inosine, and lactate/pyruvate (LP) ratio are increased and correlated in patients with acute liver failure. Furthermore, we expect the purines and L/P ratio to correlate with intracranial pressure (ICP) (positively), and cerebral perfusion pressure (CPP) (negatively)....

  5. Changes in cellular proliferation and plasma products are associated with liver failure

    Science.gov (United States)

    Melgaço, Juliana Gil; Soriani, Frederico Marianetti; Sucupira, Pedro Henrique Ferreira; Pinheiro, Leonardo Assaf; Vieira, Yasmine Rangel; de Oliveira, Jaqueline Mendes; Lewis-Ximenez, Lia Laura; Araújo, Cristina Carvalho Vianna; Pacheco-Moreira, Lúcio Filgueiras; Menezes, Gustavo Batista; Cruz, Oswaldo Gonçalves; Vitral, Claudia Lamarca; Pinto, Marcelo Alves

    2016-01-01

    AIM To study the differences in immune response and cytokine profile between acute liver failure and self-limited acute hepatitis. METHODS Forty-six patients with self-limited acute hepatitis (AH), sixteen patients with acute liver failure (ALF), and twenty-two healthy subjects were involved in this study. The inflammatory and anti-inflammatory products in plasma samples were quantified using commercial enzyme-linked immunoassays and quantitative real-time PCR. The cellular immune responses were measured by proliferation assay using flow cytometry. The groups were divided into viral- and non-viral-induced self-limited AH and ALF. Thus, we worked with five groups: Hepatitis A virus (HAV)-induced self-limited acute hepatitis (HAV-AH), HAV-induced ALF (HAV-ALF), non-viral-induced self-limited acute hepatitis (non-viral AH), non-viral-induced acute liver failure (non-viral ALF), and healthy subjects (HC). Comparisons among HAV and non-viral-induced AH and ALF were performed. RESULTS The levels of mitochondrial DNA (mtDNA) and the cytokines investigated [interleukin (IL)-6, IL-8, IL-10, interferon gamma, and tumor necrosis factor] were significantly increased in ALF patients, independently of etiology (P < 0.05). High plasma mtDNA and IL-10 were the best markers associated with ALF [mtDNA: OR = 320.5 (95%CI: 14.42-7123.33), P < 0.0001; and IL-10: OR = 18.8 (95%CI: 1.38-257.94), P = 0.028] and death [mtDNA: OR = 12.1 (95%CI: 2.57-57.07), P = 0.002; and IL-10: OR = 8.01 (95%CI: 1.26-50.97), P = 0.027]. In the cellular proliferation assay, NKbright, NKT and regulatory T cells (TReg) predominated in virus-specific stimulation in HAV-induced ALF patients with an anergic behavior in the cellular response to mitotic stimulation. Therefore, in non-viral-induced ALF, anergic behavior of activated T cells was not observed after mitotic stimulation, as expected and as described by the literature. CONCLUSION mtDNA and IL-10 may be predictors of ALF and death. TReg cells are

  6. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.

    Science.gov (United States)

    Jaeschke, Hartmut; McGill, Mitchell R; Ramachandran, Anup

    2012-02-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

  7. Results of treatment of acute liver failure patients with use of the prometheus FPSA system.

    Science.gov (United States)

    Grodzicki, M; Kotulski, M; Leonowicz, D; Zieniewicz, K; Krawczyk, M

    2009-10-01

    Herein we have presented the results of treatment of acute liver failure (ALF) patients with the use of the Prometheus FPSA dialysis system. To January 2009, we performed 278 FPSA procedures in 114 patients, including 52 experience and ALF. The patients who underwent the FPSA procedure consisted of 32 women and 20 men of overall mean age of 33 +/- 12 years. The causes of ALF were: Wilson's disease (n = 15), unknown origin ALF (n = 11), amanita phalloides intoxication (n = 7), paracetamol intoxication (n = 8), acute hepatitis B virus (HBV)/hepatitis C virus (HCV) infection (n = 7), liver insufficiency after parenchymal resection (n = 2) drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (n = 1), rabdomyolysis (n = 1), or primary nonfunction (PNF) after orthotopic liver transplantation (OLT) (n = 1). All procedures were performed using the Prometheus 4008H Fresenius Medical Care liver support system. The average number of treatments per patient was 2.41 and the average time for each FPSA treatment was 6.3 hours. The average heparin dose used during the procedure was 750 IU/h. After the whole treatment regimen, we observed significant improvements in the biochemical results. The average concentrations improved: serum ammonia (before 249.2 mug/dL versus after 109.7 mug/dL); serum bilirubin (before 21.53 mg/dL versus after 8.81 mg/dL), serum aspartate aminotransferase (AST; before 2456.4 U/L versus after 1068.8 U/L); serum alanine aminotransferase (ALT; before 2958.2 U/L versus after 1595.8 U/L); serum urea (before 58.5 mg/dL versus after 21.1 mg/dL); serum creatinine (before 2.9 mg/dL versus after 1.7 mg/dL); and pH value (before 7.11 versus after 7.32). After Prometheus treatment OLT was performed in 33 patients. Among the 28 who survived (53.8%), 22 underwent OLT and 6 did not have OLT. Among the 24 patients who died (46.2%), 13 were before OLT and 11 after OLT. The Prometheus 4008H Fresenius Medical Care Liver support system was useful method of

  8. Bone mesenchymal stem cell transplantation via four routes for the treatment of acute liver failure in rats.

    Science.gov (United States)

    Sun, Lihua; Fan, Xiaotang; Zhang, Lijuan; Shi, Guixiu; Aili, Maimaiti; Lu, Xiaobo; Jiang, Tao; Zhang, Yuexin

    2014-10-01

    In the present study, we assessed the efficiency of four BMSC transplantation methods as a therapy for liver failure. A rat model (80 Sprague-Dawley rats) of D-galactosamine (D-gal)/lipopolysaccharide (LPS)-induced acute liver failure (ALF) was established and the rats were divided into 5 groups: a hepatic artery injection group, a portal vein injection group, a vena caudalis injection group, an intraperitoneal injection group and a control group (16 per group). Following transplantation, the liver tissue and blood samples were collected on days 1, 3 and 7, we detected the EdU (5-ethynyl-2'-deoxyuridine)-labeled cells homing to the liver tissue and assessed the proliferating cell nuclear antigen (PCNA) and cysteine-containing aspartate-specific protease (caspase)-3 expression in the liver tissue and detected the levels of stromal cell-derived factor 1 (SDF-1) and hepatocyte growth factor (HGF) in the liver tissues. Compared with the control group, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and damage to the liver tissue in the hepatic artery group, the portal vein group and the vena caudalis group improved in vivo. The expression of PCNA and HGF in the liver was higher and caspase-3 expression was lower in the hepatic artery injection group, the portal vein injection group and the vena caudalis injection group than that in the intraperitoneal injection and control groups. The EdU-labeled BMSCs were only observed homing to the liver tissue in these three groups. However, no significant differences were observed between these three groups. Liver function in the rats with ALF was improved following BMSC transplantation via 3 endovascular implantation methods (through the hepatic artery, portal vein and vena caudalis). These 3 methods were effective in transplanting BMSCs for the treatment of ALF. However, the selection of blood vessel in the implantation pathway does not affect the transplantation outcome. Transplantation via

  9. Extracorporeal portal vein oxygenation improves outcome of acute liver failure in swine.

    Science.gov (United States)

    Nardo, B; Tsivian, M; Neri, F; Piras, G; Pariali, M; Bertelli, R; Cavallari, G

    2008-01-01

    Portal vein arterialization (PVA) has shown efficacy to treat acute liver failure (ALF) in preclinical studies. The next step is to perform large animal studies that propose a clinically acceptable method of PVA. In this study, we assessed the efficacy of PVA using an extracorporeal device to treat 2 ALF models in swine. The 2 ALF swine models were carbon tetrachloride toxic ALF and subtotal hepatectomy using 8 animals per group. PVA was performed with an extracorporeal device that may be suitable for future clinical studies. Arterial blood was drawn from the iliac artery and delivered into the portal vein for a 6-hour treatment. We analyzed biochemical, blood gas, and histological parameters as well as 1-week survival rates. In both models, ALF was successfully achieved. Control group animals deteriorated biochemically, dropping their prothrombin times and increasing the liver enzymes. In contrast, treated animals improved with a survival rate of 75% at 7 days compared with 0% for the former group. PVA using an extracorporeal device was feasible and effective to treat both toxic and resective ALF in swine.

  10. Transplantation of human stem cell-derived hepatocytes in an animal model of acute liver failure.

    Science.gov (United States)

    Ramanathan, Rajesh; Pettinato, Giuseppe; Beeston, John T; Lee, David D; Wen, Xuejun; Mangino, Martin J; Fisher, Robert A

    2015-08-01

    Hepatocyte cell transplantation can be life-saving in patients with acute liver failure (ALF); however, primary human hepatocyte transplantation is limited by the scarcity of donor hepatocytes. We investigated the effect of stem cell-derived, hepatocyte-like cells in an animal xenotransplant model of ALF. Intraperitoneal d-galactosamine was used to develop a lethal model of ALF in the rat. Human induced pluripotent stem cells (iPSC), human mesenchymal stem cells, and human iPSC combined with human endothelial cells (iPSC + EC) were differentiated into hepatocyte-like cells and transplanted into the spleens of athymic nude rats with ALF. A reproducible lethal model of ALF was achieved with nearly 90% death within 3 days. Compared with negative controls, rats transplanted with stem cell-derived, hepatocyte-like cells were associated with increased survival. Human albumin was detected in the rat serum 3 days after transplantation in more than one-half the animals transplanted with hepatocyte-like cells. Only animals transplanted with iPSC + EC-derived hepatocytes had serum human albumin at 14 days posttransplant. Transplanted hepatocyte-like cells homed to the injured rat liver, whereas the ECs were only detected in the spleen. Transplantation of stem cell-derived, hepatocyte-like cells improved survival with evidence of in vivo human albumin production. Combining ECs may prolong cell function after transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.

    Science.gov (United States)

    Romero-Gómez, Manuel; Montagnese, Sara; Jalan, Rajiv

    2015-02-01

    Hepatic encephalopathy in a hospitalized cirrhotic patient is associated with a high mortality rate and its presence adds further to the mortality of patients with acute-on-chronic liver failure (ACLF). The exact pathophysiological mechanisms of HE in this group of patients are unclear but hyperammonemia, systemic inflammation (including sepsis, bacterial translocation, and insulin resistance) and oxidative stress, modulated by glutaminase gene alteration, remain as key factors. Moreover, alcohol misuse, hyponatremia, renal insufficiency, and microbiota are actively explored. HE diagnosis requires exclusion of other causes of neurological, metabolic and psychiatric dysfunction. Hospitalization in the ICU should be considered in every patient with overt HE, but particularly if this is associated with ACLF. Precipitating factors should be identified and treated as required. Evidence-based specific management options are limited to bowel cleansing and non-absorbable antibiotics. Ammonia lowering drugs, such as glycerol phenylbutyrate and ornithine phenylacetate show promise but are still in clinical trials. Albumin dialysis may be useful in refractory cases. Antibiotics, prebiotics, and treatment of diabetes reduce systemic inflammation. Where possible and not contraindicated, large portal-systemic shunts may be embolized but liver transplantation is the most definitive step in the management of HE in this setting. HE in patients with ACLF appears to be clinically and pathophysiologically distinct from that of acute decompensation and requires further studies and characterization.

  12. Hepatitis A as an etiologic agent of acute liver failure in Latin America.

    Science.gov (United States)

    Ciocca, Mirta; Moreira-Silva, Sandra Fagundes; Alegría, Sylvia; Galoppo, Maria Cristina; Ruttiman, Ricardo; Porta, Gilda; Da Silvera, Themis Reverbel; Rubio, Pilar; Macias, Mercedes; Cervantes, Yolanda; Avila-Aguero, Maria Luisa; Clemens, Sue Anne Costa; Clemens, Ralf; Weil, John

    2007-08-01

    This prospective, multicenter study examined the importance of hepatitis viruses as etiological agents of acute liver failure (ALF) and the outcome of ALF cases in Latin American children and adolescents. The study was conducted for minimum 12 months in 9 centers in Argentina, Brazil, Chile, Colombia, Costa Rica, and Mexico during 2001-2002. Hospitalized patients aged 1-20 years with a suspected diagnosis of ALF were included in the study and tested for serologic markers for hepatitis A, B, and C viruses. Of the 106 patients enrolled, 88 were included in the analysis. Median age was 5 years, and 55% with ALF were aged 1-5 years. A total of 37 individuals (43%) tested positive for anti-hepatitis A virus (HAV) immunoglobulin M (IgM) as marker of acute HAV infection; one was positive for anti-hepatitis B core antigen IgM and negative for hepatitis B surface antigen. None had markers of hepatitis C virus infection. Mortality rates in the overall study cohort (45%) and for those who tested anti-HAV IgM positive (41%) were similar. Forty-one percent of all patients and 46% of those positive for anti-HAV IgM underwent transplantation. The mortality rate in those with liver transplantation was half of that in patients who were not transplanted (28% versus 57%). HAV was the main etiologic agent of ALF in the population studied.

  13. Assessment of Erythropoietin Levels and Some Iron Indices in Chronic Renal Failure and Liver Cirrhosis Patients

    Directory of Open Access Journals (Sweden)

    Essam Mady

    1999-01-01

    Full Text Available This study was constructed to investigate the relationship between renal anaemia and erythropoietin (EPO concentrations in chronic renal failure (CRF patients and to evaluate the possible role of the liver. Serum EPO levels were measured in blood samples from 20 CRF patients on hemodialysis (HD, 20 liver cirrhosis (LC patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Blood cell counts, iron indices (iron, total iron-binding capacity (TIBC and ferritin, renal function (blood urea nitrogen (BUN and creatinine, hepatic function (ALT, AST, ALP and bilirubin investigations were carried out for all the subjects enrolled in this study. CRF patients without LC had serum EPO concentration of 6.21 ± 0.53 mU/ml (mean ± SE, which was significantly higher than that in patients having both CRF and LC (4.32 ± 0.52 (p < 0.01. Both groups showed significantly lower values than the controls (12.75 ± 0.70 (p < 0.001. LC patients with intact kidneys had significantly higher EPO level (22.70 ± 1.70 (p < 0.001. No correlation was found between EPO level and any of the hematologic or iron indices.

  14. MicroRNA-125b-5p mimic inhibits acute liver failure

    Science.gov (United States)

    Yang, Dakai; Yuan, Qinggong; Balakrishnan, Asha; Bantel, Heike; Klusmann, Jan-Henning; Manns, Michael P.; Ott, Michael; Cantz, Tobias; Sharma, Amar Deep

    2016-01-01

    The lack of broad-spectrum anti-acute liver failure (ALF) therapeutic agents contributes to ALF-related mortality. MicroRNAs (miRNAs) are suggested to be potent serum biomarkers for ALF, but their functional and therapeutic relevance in ALF are unclear. Here we show an unbiased approach, using two complementary miRNA screens, to identify miRNAs that can attenuate ALF. We identify miR-125b-5p as a regulator of cell death that attenuates paracetamol-induced and FAS-induced toxicity in mouse and human hepatocytes. Importantly, administration of miR-125b-5p mimic in mouse liver prevents injury and improves survival in models of ALF. Functional studies show that miR-125b-5p ameliorates ALF by directly regulating kelch-like ECH-associated protein 1, in turn elevating expression of nuclear factor-E2-related factor 2, a known regulator in ALF. Collectively, our findings establish miR-125b-5p as an important regulator of paracetamol-induced and FAS-induced cell death. Thus, miR-125b-5p mimic may serve as a broad-spectrum therapeutic attenuator of cell death during ALF. PMID:27336362

  15. Liver Function, In-Hospital, and Post-Discharge Clinical Outcome in Patients With Acute Heart Failure-Results From the Relaxin for the Treatment of Patients With Acute Heart Failure Study

    NARCIS (Netherlands)

    van Deursen, Vincent M.; Edwards, Christopher; Cotter, Gad; Davison, Beth A.; Damman, Kevin; Teerlink, John R.; Metra, Marco; Felker, G. Michael; Ponikowski, Piotr; Unemori, Elaine; Severin, Thomas; Voors, Adriaan A.

    2014-01-01

    Background: Elevated plasma concentrations of liver function tests are prevalent in patients with chronic heart failure (HF). Little is known about liver function in patients with acute HF. We aimed to assess the prevalence and prognostic value of serial measurements of liver function tests in patie

  16. Whole Blood Polymerase Chain Reaction in a Neonate with Disseminated Herpes Simplex Virus Infection and Liver Failure

    Directory of Open Access Journals (Sweden)

    Jennifer A. Scoble

    2013-10-01

    Full Text Available A late preterm neonate born by cesarean section with intact membranes presented at 9 days of life with shock and liver failure. Surface cultures were negative but whole blood polymerase chain reaction was positive for herpes simplex virus type 2, underscoring the value of this test in early diagnosis of perinatally acquired disseminated herpes simplex virus infection without skin lesions.

  17. Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study.

    Science.gov (United States)

    Kaffarnik, Magnus F; Ahmadi, Navid; Lock, Johan F; Wuensch, Tilo; Pratschke, Johann; Stockmann, Martin; Malinowski, Maciej

    2017-01-01

    To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients. 28 septic patients (8 female, 20 male, age range 35-80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test. Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001). Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.

  18. Life Saving Plasmapheresis for the Management of Hemolytic Crisis and Acute Liver Failure in Wilson’s Disease

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Pashaei

    2009-06-01

    Full Text Available Wilson's disease, caused by a deficient cellular copper export system, is transmitted as an autosomal recessive inherited disorder and results in copper accumulation in liver and other organs, particularly in brain. Acute hepatic failure and severe Coombs' negative hemolysis may occur in the course of the disease which has a poor prognosis and most patients do not survive the crisis. Only liver transplantation has been recommended as an effective medical intervention. Herein, we presented a 25-year-old woman with impaired consciousness, acute hepatic failure and hemolysis who was treated with plasmapheresis and albumin replacement. Beside improvement in medical condition, serum copper and hemolysis decreased significantly and renal function was preserved. We concluded that plasmapheresis may be a life saving intervention during fulminant hepatic failure of Wilson's disease.

  19. Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats

    Institute of Scientific and Technical Information of China (English)

    Lu-Wen Wang; Li-Kun Wang; Hui Chen; Cheng Fan; Xun Li; Can-Ming He; Zuo-Jiong Gong

    2012-01-01

    AIM:To investigate the protective effects of ethyl pyruvate (EP) on acute-on-chronic liver failure (ACLF) in METHODS:An ACLF model was established in rats,and animals were randomly divided into normal,model and EP treatment groups.The rats in EP treatment group received EP (40 mg/kg) at 3 h,6 h,12 h and 24 h after induction of ACLF.Serum endotoxin,high mobility group box-1 (HMGB1),alanine transaminase (ALT),tumor necrosis factor-α (TNF-α),interferon-α (IFN-y),interleukin (IL)-10 and IL-18 levels,changes of liver histology and HMGB1 expressions in liver tissues were detected at 48 h after induction of ACLF.The effects of EP on the survival of ACLF rats were also observed.RESULTS:Serum levels of endotoxin (0.394 ± 0.066 EU/mL vs 0.086 ± 0.017 EU/mL,P < 0.001),HMGB1 (35.42 ± 10.86 μg/L vs 2.14 ± 0.27 μg/L,P < 0.001),ALT (8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L,P < 0.001),TNF-α (190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L,P < 0.001),IFN-γ (715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L,P < 0.001),IL-10 (6.85 ± 0.64ng/L vs 3.49 ± 0.24 ng/L,P < 0.001) and IL-18 (85.19± 3.49 ng/L vs 55.38 ± 1.25 ng/L,P < 0.001) were significantly increased,and liver tissues presented severe pathological injury in the model group compared with the normal group.However,EP administration significantly improved hepatic histopathology and reduced the serum levels of endotoxin (0.155 ± 0.045 EU/mL vs 0.394-0.066 EU/mL,P < 0.001) and inflammatory cytokines (11.13 ± 2.58 μg/L vs 35.42± 10.86 μg/L for HMGB1,3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT,128.55 ± 5.76 ng/L vs 190.77-12.34 ng/L for TNF-α,438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-y,3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10,and 60.35 ± 1.63ng/L vs 85.19 ± 3.49 ng/L for IL-18,respectively,P < 0.001),and the levels of HMGB1 in liver tissues regardless of treatment time after induction of ACLF.EP treatment at the four time points prolonged the median survival time

  20. Different effects of selective β1-adrenoceptor antagonists, nebivolol or atenolol in acetaminophen-induced hepatotoxicity of rats.

    Science.gov (United States)

    Rofaeil, Remon R; Kamel, Maha Y; Abdelzaher, Walaa Y

    2017-04-01

    Acetaminophen (APAP) overdose is a common cause of acute liver failure, and beta-blockers are commonly used drugs in clinical practice. This study aimed to evaluate the effect of two different beta-blocker agents as nebivolol and atenolol against APAP-induced hepatotoxicity. Male Wistar rats were treated with APAP (2 g/kg/day, p.o.) to induce hepatotoxicity. Our results showed that nebivolol and atenolol reduced heart rate and blood pressure. Nebivolol (5 mg/kg/day, p.o.) for 14 days has a hepatoprotective effect shown by significant decrease in hepatic injury parameters (serum AST and ALT) with significant suppression of hepatic malondialdehyde (MDA) and nitric oxide (NO) which were elevated with APAP administration. Also, nebivolol increased reduced glutathione (GSH) which was reduced with APAP administration. Moreover, immunohistochemical examination revealed that nebivolol treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced, as compared to APAP group. The protective effects of nebivolol were also verified histopathologically. On the other hand, as compared to APAP group, oral administration of atenolol (50 mg/kg) increased hepatic injury parameters but did not change hepatic NO, MDA, and GSH. In conclusion, this study revealed that nebivolol not atenolol is protective against APAP-induced hepatotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS expression. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  1. Liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti-tubercular treatment.

    Science.gov (United States)

    Bartoletti, Michele; Martelli, Giulia; Tedeschi, Sara; Morelli, Mariacristina; Bertuzzo, Valentine; Tadolini, Marina; Pianta, Paolo; Cristini, Francesco; Giannella, Maddalena; Lewis, Russell E; Pinna, Antonio D; Viale, Pierluigi

    2017-04-01

    Active tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario. We described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity. TB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (Ptreatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia.

    Science.gov (United States)

    Jamshidzadeh, Akram; Heidari, Reza; Abasvali, Mozhgan; Zarei, Mehdi; Ommati, Mohammad Mehdi; Abdoli, Narges; Khodaei, Forouzan; Yeganeh, Yasaman; Jafari, Faezeh; Zarei, Azita; Latifpour, Zahra; Mardani, Elnaz; Azarpira, Negar; Asadi, Behnam; Najibi, Asma

    2017-02-01

    Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats.

    Science.gov (United States)

    Demirel, Ulvi; Yalniz, Mehmet; Aygün, Cem; Orhan, Cemal; Tuzcu, Mehmet; Sahin, Kazim; Ozercan, Ibrahim Hanifi; Bahçecioğlu, Ibrahim Halil

    2012-08-01

    Oxidative stress plays important role in the development of acute liver failure. In this study, we investigated effects of allopurinol (AP) upon thioacetamide (TAA)-induced liver injury and the potential mechanisms leading to amelioration in inflammation with AP treatment. Acute liver failure was induced by intraperitoneal administration of TAA (300 mg/kg/day for 2 days). Thirty-five rats were divided into five groups as control (group 1), TAA (group 2), TAA + 25AP (group 3), TAA + 50 AP (group 4), and TAA + 100AP (group 5). The number of animals in each group was seven. At the end of the study, histopathological, biochemical, and western blot analysis were done. TAA treatment significantly increased serum levels of aminotransferases, liver malondialdehyde (MDA), nuclear factor-kappa B (NF-қB ), activator protein-1 (AP-1), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) levels, and the necro-inflammation scores. Nevertheless, nuclear factor E2-related factor-2 and heme oxygenase-1 (HO-1) expressions in the liver were decreased by TAA. AP treatment significantly lowered the serum levels of aminotransferases (P < 0.01) and liver MDA, NF-κB, AP-1, TNF-α, COX-2, and IL-6 expressions (P < 0.05). Moreover, AP restored the liver Nrf2 and HO-1 expressions and improved the necro-inflammation scores significantly. AP improves oxidative stress-induced liver damage by regulating cellular redox-sensitive transcriptor factors and expression of pro-inflammatory and antioxidant defense mechanisms. AP probably exerts these beneficiary features by its free radical scavenging ability in a dose-dependent manner.

  4. Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure: A Propensity-Score Matched Population-Based Retrospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Stephen R Knight

    Full Text Available Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy.A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011 with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use.Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (P<0.001 and P = 0.009 respectively, n = 725. In a Cox proportional hazards model, renal replacement therapy was a predictor of both patient death (hazard ratio (HR 1.59, 95% CI 1.01-2.50, P = 0.044 but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114. In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy.In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial.

  5. Benign Liver Tumors

    Science.gov (United States)

    ... A Life After Diagnosis Support for Chronic Illness Corporate Partnerships Interview with Kristen Hanks Liver Lowdown July ... Disease , Liver Transplant , Liver Cancer , Liver Tumor , Liver Failure Help Fight Liver Disease We rely upon donations ...

  6. Acute liver failure in a term neonate after repeated paracetamol administration

    Directory of Open Access Journals (Sweden)

    Fabio Bucaretchi

    2014-03-01

    Full Text Available Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L, hypoglycemia (18mg/dL, increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL after receiving oral paracetamol (10mg/kg/dose every 4 hours for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL. Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.

  7. Changes of gut flora and endotoxin in rats with D-galactosamine-induced acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Lan-Juan Li; Zhong-Wen Wu; Dang-Sheng Xiao; Ji-Fang Sheng

    2004-01-01

    AIM: To investigate the changes of gut microflora and endotoxin levels in rats with acute liver failure (ALF) induced by D-galactosamine (GalN).METHODS: Flora and endotoxin levels in the jejunum, ileum and colon in normal rats (group A) and rats with GalNinduced ALF were determined at 24 h (group B) or 48 h (group C) after GalN injection, as well as the endotoxin level in portal venous blood (PVB) and right ventricle blood (RVB) were determined by chromogenic limulus amoebocyte assay.RESULTS: Intestinal (jejunum, ileum, colon)lactobacillus count was statistically reduced in group B compared with those in group A (3.4±0.3 vs4.9±0.3, 6.1±0.4 vs 8.0±0.3,8.1±0.2 vs 9.3±0.2, P<0.001, P<0.001 and P<0.001respectively) and recovered partially in the group C compared with those in the group B, whereas the count of Enterobacteriaceae in the jejunum, ileum and colon in group B was increased markedly compared with those in the group A (5.1±0.3 vs 3.6±0.2, 6.9±0.5 vs 5.3±0.3,8.7±0.2 vs7.6±0.1, P<0.001, P<0.05 and P<0.05 respectively)and restored partially in the group C compared with those in the group B. The endotoxin level in ileum was increased in the group B compared with those in the group A (111.3±22.8 vs 51.5±8.9, P<0.05). In addition, the endotoxin level in PVB was obviously increased in group B compared with that in the group A (76.8±9.1 vs40.6±7.3,P<0.01) and reduced to the baseline at 48 h (group C).CONCLUSIOM: Severely disturbed gut flora in rats with GalN-induced acute liver failure plays an important role in the elevation of endotoxin level in PVB.

  8. Acute liver failure due to concomitant arterial, portal and biliary injury during laparoscopic cholecystectomy: is transplantation a valid life-saving strategy? A case report

    Directory of Open Access Journals (Sweden)

    Goldaracena Nicolas

    2009-09-01

    Full Text Available Abstract Background Combined iatrogenic vascular and biliary injury during cholecystectomy resulting in ischemic hepatic necrosis is a very rare cause of acute liver failure. We describe a patient who developed fulminant liver failure as a result of severe cholestasis and liver gangrene secondary to iatrogenic combine injury or the hepatic pedicle (i.e. hepatic artery, portal vein and bile duct during laparoscopic cholecystectomy. Case presentation A 40-years-old woman underwent laparoscopic cholecystectomy for acute cholecystitis. During laparoscopy, a severe bleeding at the liver hilum motivated the conversion to open surgery. Many sutures were placed across the parenchyma for bleeding control. After 48 hours, she rapidly deteriorated with encephalopathy, coagulopathy, persistent hypotension and progressive organ dysfunction including acute renal failure requiring hemodialysis and mechanical ventilation. An angiography documented an occlusion of right hepatic artery and right portal vein. In the clinical of acute liver failure secondary to liver gangrene, severe coagulopathy and progressive secondary multi-organ failure, the patient was included in the waiting list for liver transplantation. Two days later, the patient was successfully transplanted with initial adequate liver graft function. However, she developed bilateral pneumonia and severe gastrointestinal bleeding and finally died 24 days after transplantation due to bilateral necrotizing pneumonia. Conclusion The occurrence of acute liver failure due to portal triad injury during laparoscopic cholecystectomy is a catastrophic complication. Probably, the indication of liver transplantation as a life-saving strategy in patients with late diagnosis, acute liver failure, severe coagulopathy and progressive secondary multi-organ failure could be considered but only minimizing immunosuppressive regimen to avoid postoperative infections.

  9. Efficacy of a chronic disease management model for patients with chronic liver failure.

    Science.gov (United States)

    Wigg, Alan J; McCormick, Rosemary; Wundke, Rachel; Woodman, Richard J

    2013-07-01

    Despite the economic impacts of chronic liver failure (CLF) and the success of chronic disease management (CDM) programs in routine clinical practice, there have been no randomized controlled trials of CDM for CLF. We investigated the efficacy of CDM programs for CLF patients in a prospective, controlled trial. Sixty consecutive patients with cirrhosis and complications from CLF were assigned randomly to groups given intervention (n = 40) or usual care (n = 20), from 2009 to 2010. The 12-month intervention comprised 4 CDM components: delivery system redesign, self-management support, decision support, and clinical information systems. The primary outcome was the number of days spent in a hospital bed for liver-related reasons. Secondary outcomes were rates of other hospital use measures, rate of attendance at planned outpatient care, disease severity, quality of life, and quality of care. The intervention did not reduce the number of days patients spent in hospital beds for liver-related reasons, compared with usual care (17.8 vs 11.0 bed days/person/y, respectively; incidence rate ratio, 1.6; 95% confidence interval, 0.5-4.8; P = .39), or affect other measures of hospitalization. Patients given the intervention had a 30% higher rate of attendance at outpatient care (incidence rate ratio, 1.3; 95% confidence interval, 1.1-1.5; P = .004) and significant increases in quality of care, based on adherence to hepatoma screening, osteoporosis and vaccination guidelines, and referral to transplant centers (P < .05 for all). In a pilot study to determine the efficacy of CDM for patients with CLF, patients receiving CDM had significant increases in attendance at outpatient centers and quality of care, compared with patients who did not receive CDM. However, CDM did not appear to reduce hospital admission rates or disease severity or improve patient quality of life. Larger trials with longer follow-up periods are required to confirm these findings and assess cost

  10. Liver support therapy with molecular adsorbents recirculating system in liver failure:a summary of 252 cases from 14 centers in China

    Institute of Scientific and Technical Information of China (English)

    WANG Min-min; HU Xiao-bin; LUO Hong-tao; LIU Yi-he; WANG Wen-ya; CHEN Shi-jun; YE Qi-fa; YANG Yi-jun; CHEN Shi-bin; ZHOU Xin-min; GUO Li-min; ZHANG Yue-xin; DING Xiao-qiang

    2008-01-01

    Background A liver support therapy,named molecular adsorbents recirculating system (MARS),has been used for more than 700 liver failure patients in China.We made here a summary to evaluate the effects of MARS treatment in different applications with emphasis on hepatitis B virus (HBV) based liver failure.Methods This report analyzed data of 252 patients (mean age (44.9±12.7) years) in three groups:acute severe hepatitis (ASH),subacute severe hepatitis (SSH) and chronic severe hepatitis (CSH).The largest group was CSH (156 patients,61.9%),and 188 patients (74.6%,188/252) were infected with HBV.Results MARS treatments were associated with significant reduction of albumin bound toxins and water-soluble toxins.Most of the patients showed a positive response with a significant improvement of multiple organ function substantiated by a significant increase in prothrombin time activity (PTA) and median arterial pressure (MAP).There was a decrease in hepatic encephalopathy (HE) grade and Child-Turcotte-Pugh (CTP) scale.Thirty-nine of 188 HBV patients (20.7%) dropped out of the commendatory consecutive therapy ending with lower survival of 43.6% while the rest of the 149 patients had a survival rate of 62.4%.Survival within the ASH and SSH groups were 81.2% and 75.0%,respectively.In the CSH group,end stage patients were predominant (65/151,43%),whereas the early and middle stage patients had a better prognosis:early stage survival,including orthotopic liver transplantation (OLT) survival of 91.7%,middle stage survival of 75%,end stage survival of 33.8%.Conclusions MARS continues to be the most favorable extracorporeal treatment for liver support therapy in China for a wide range of conditions,including the majority of hepatitis B related liver failure conditions.The appropriate application of MARS for the right indications and stage of hepatic failure,as well as the fulfillment of prescribed treatments,will lead to the optimal therapeutic result.

  11. Cerebral glutamine concentration and lactate-pyruvate ratio in patients with acute liver failure

    DEFF Research Database (Denmark)

    Bjerring, P.N.; Hauerberg, J.; Frederiksen, Hans-Jørgen;

    2008-01-01

    AIM: Hyperammonemia causes brain edema and high intracranial pressure (ICP) in acute liver failure (ALF) by accumulation of glutamine in brain. Since a high-level glutamine may compromise mitochondrial function, the aim of this study was to determine if the lactate-pyruvate ratio is associated...... with a rise in the glutamine concentration and ICP. PATIENTS AND METHODS: In 13 patients with ALF (8F/5M; median age 46 (range 18-66) years) the cerebral extracellular concentrations of glutamine, lactate, and pyruvate were measured by in vivo brain microdialysis together with ICP and cerebral perfusion...... pressure (CPP). RESULTS: The cerebral glutamine concentration was 4,396 (1,011-9,712) microM, lactate 2.15 (1.1-4.45) mM, and pyruvate 101 (43-255) microM. The lactate-pyruvate ratio was 21 (16-40), ICP 20 (2-28) mmHg, and CPP 72 (56-115) mmHg. Cerebral glutamine concentration correlated with the lactate...

  12. Impaired gluconeogenesis in a porcine model of paracetamol induced acute liver failure

    Institute of Scientific and Technical Information of China (English)

    Konstantinos J Dabos; Henry R Whalen; Philip N Newsome; John A Parkinson; Neil C Henderson; Ian H Sadler; Peter C Hayes; John N Plevris

    2011-01-01

    AIM: To investigate glucose homeostasis and in particular gluconeogenesis in a large animal model of acute liver failure (ALF). METHODS: Six pigs with paracetamol induced ALF under general anaesthesia were studied over 25 h. Plasma samples were withdrawn every five hours from a central vein. Three animals were used as controls and were maintained under anaesthesia only. Using 1H NMR spectroscopy we identified most gluconeogenic amino acids along with lactate and pyruvate in the animal plasma samples. RESULTS: No significant changes were observed in the concentrations of the amino acids studied in the animals maintained under anaesthesia only. If we look at the ALF animals, we observed a statistically significant rise of lactate (P < 0.003) and pyruvate (P < 0.018) at the end of the experiments. We also observed statistically significant rises in the concentrations of alanine (P < 0.002), glycine (P < 0.005), threonine (P < 0.048), tyrosine (P < 0.000), phenylalanine (P < 0.000) and isoleucine (P < 0.01). Valine levels decreased significantly (P < 0.05). CONCLUSION: Our pig model of ALF is characterized by an altered gluconeogenetic capacity, an impaired tricarboxylic acid (TCA) cycle and a glycolytic state.

  13. Soluble CD163 from activated macrophages predicts mortality in acute liver failure

    DEFF Research Database (Denmark)

    Møller, Holger Jon; Grønbaek, Henning; Schiødt, Frank V

    2007-01-01

    BACKGROUND/AIMS: Soluble CD163 (sCD163) is a scavenger receptor shed in serum during inflammatory activation of macrophages. We investigated if sCD163 was increased and predicted outcome in acute liver failure (ALF). METHODS: Samples from 100 consecutive patients enrolled in the U.S. ALF Study...... Group for whom sera were available were collected on days 1 and 3, and clinical data were obtained prospectively. sCD163 levels were determined by ELISA. RESULTS: The median level of sCD163 was significantly increased in ALF (21.1mg/l (range 3.6-74.9)) as compared to healthy controls (2.3mg/l (0.......65-5.6), pCD163 on day 1 correlated significantly with ALT, AST, bilirubin, and creatinine. sCD163 concentrations on day 3 were elevated in patients with fatal outcome of disease compared to spontaneous survivors, 29.0mg/l (7...

  14. Does the standard vs piggyback surgical technique affect the development of early acute renal failure after orthotopic liver transplantation?

    Science.gov (United States)

    Cabezuelo, J B; Ramirez, P; Acosta, F; Torres, D; Sansano, T; Pons, J A; Bru, M; Montoya, M; Rios, A; Sánchez Bueno, F; Robles, R; Parrilla, P

    2003-08-01

    The objective of this study was to evaluate the effect of the surgical technique on postoperative renal function during the first week after liver transplantation (OLT). We performed a retrospective study of 184 consecutive OLT. Criteria for acute renal failure were: serum creatinine >1.5 mg/dL, an increase by 50% in the baseline serum creatinine, or oliguria requiring renal replacement therapy. The distribution of patients according to the surgical technique was: standard (n=84), venovenous bypass (n=20), and piggyback (n=80). Other variables analyzed were: intraoperative requirement for blood products, treatment with adrenergic agonists, intraoperative complications, and postreperfusion syndrome. Univariate analysis showed the following parameters to be significantly related to postoperative renal failure: intraoperative fresh frozen plasma and cryoprecipitate requirements, intraoperative complications, postreperfusion syndrome, need for noradrenaline or dobutamine, standard surgical technique versus piggyback (39% vs 18%, P20 U cryoprecipitate requirement (OR=1.04, P=.01). In conclusion, compared with the piggyback technique, the standard surgical technique appears to be an independent risk factor for postoperative acute renal failure. When venovenous bypass is used in patients who do not tolerate trial clamping of inferior vena cava, it does not reduce the incidence of postoperative renal failure. Finally, the piggyback technique significantly reduces the probability of acute renal failure after liver transplantation.

  15. Liver transplantation for acute liver failure: a 5 years experience Transplante hepático na hepatite fulminante: uma experiência de 5 anos

    Directory of Open Access Journals (Sweden)

    Cyntia Ferreira Gomes Viana

    2008-09-01

    Full Text Available BACKGROUND: Fulminant hepatic failure carries a high morbidity and mortality. Liver transplantation has markedly improved the prognosis of patients with fulminant hepatic failure. AIM: To evaluate the outcome of 20 patients with acute liver failure and indication for liver transplantation. METHODS: A retrospective review of 20 patients with acute liver failure and indication for liver transplantation was performed. Patients were divided into two groups: group A with 12 patients who underwent liver transplantation and group B with 8 patients who did not receive liver transplantation. Both groups were analyzed according to age, sex, ABO blood type, etiology of acute liver failure, time on list until transplantation or death, and survival rates. Group A patients were additionally analyzed according to preoperative INR, AST, and ALT peak values and MELD (Model for End-stage Liver Disease scores; intraoperative red blood cells and plasma transfusion and cold ischemia time; postoperative lenght of intensive care unit and hospital stay, and needed for dialysis. RESULTS: Group A: there were four men and eight women with an average age of 24.6 years. The average liver waiting time period was 3.4 days and MELD score 36. Seven patients are alive with good hepatic function at a medium follow-up of 26.2 months. The actuarial survival rate was 65.2% at 1 year. Group B: There were two men and six women with an average age of 30.9 years. The mean waiting time on list until death was 7.4 days. All patients died while waiting for a liver donor. CONCLUSION: Despite the improvements in intensive care management, most patients with acute liver failure and indication for liver transplantation ca not survive long without transplant. Liver transplantation is potentially the only curative modality and has markedly improved the prognosis of those patients.RACIONAL: OBJETIVO: Avaliar a evolução de 20 pacientes com insuficiência hepática aguda e indicação de

  16. Comparison scoring model of severe viral hepatitis and model of end stage liver disease for the prognosis of patients with liver failure in China

    Institute of Scientific and Technical Information of China (English)

    Li Zhou; Pei-Ling Dong; Hui-Guo Ding

    2007-01-01

    AIM: To estimate the prognosis of patients with liver failure using a scoring model of severe viral hepatitis (SMSVH) and a model of end stage liver disease (MELD)to provide a scientific basis for clinical decision of treatment.METHODS: One hundred and twenty patients with liver failure due to severe viral hepatitis were investigated with SMSVH established. Patients with acute, subacute,and chronic liver failure were 40, 46 and 34, respectively.The follow-up time was 6 mo. The survival rates of patients with liver failure in 2 wk, 4 wk, 3 mo and 6 mo were estimated with Kaplan-Meier method. Comparison between SMSVH and MELD was made using ROC statistic analysis.RESULTS: The survival curves of group A (at low risk,SMSVH score ≤ 4) and group B (at high risk, SMSVH score ≥ 5) were significantly different (The 4-wk, 3-mo, 6-mo survival rates were 94.59%, 54.05%, 43.24% in group A,and 51.81%, 20.48%, 12.05% in group B, respectively,P < 0.001). The survival curves of group C (SMSVH scores unchanged or increased), group D (SMSVH scores decreased by 1) and group E (SMSVH scores decreased by 2 or more) were significantly different .The survival rates of groups C, D and E were 66.15%, 100%, 100% in 2-wk; 40.0%, 91.18%, 100% in 4-wk; 0%, 58.82%,80.95% in 3-mo and 0%, 38.24%, 61.90% in 6-mo,respectively, P < 0.001). The area under the ROC curve (AUC) of SMSVH scores at baseline and after 2 wk of therapy was significantly higher than that under the ROC curve of MELD scores (0.804 and 0.934 vs 0.689, P <0.001).CONCLUSION: SMSVH is superior to MELD in the estimation of the prognosis of patients with severe viral hepatitis within 6 mo. SMSVH may be regarded as a criterion for estimation of the efficacy of medical treatment and the decision of clinical treatment.

  17. Effects of haemoperfusion through charcoal or XAD-2 resin on an animal model of fulminant liver failure

    Science.gov (United States)

    Weston, M. J.; Gazzard, B. G.; Buxton, B. H.; Winch, J.; Machado, A. L.; Flax, H.; Williams, Roger

    1974-01-01

    In a group of dogs in whom fulminant liver failure had been induced, perfusion of blood through activated charcoal resulted in a significantly longer survival than that of a similar group of dogs whose blood was not so treated. An otherwise progressive rise in blood ammonia concentration was halted in the treatment group. In another group of dogs with fulminant liver failure perfusion of blood through the resin Amberlite XAD-2 was associated with a fall in the serum bilirubin concentration and complete clearance from the blood of 14C-labelled sodium glycocholate. Survival in this group of animals was not significantly prolonged. This was due at least in part to the occurrence of haemorrhage due to thrombocytopenia. Platelets adhere to the resin but do not adhere to the same degree to charcoal coated with a thin layer of polymer. PMID:4851751

  18. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure

    DEFF Research Database (Denmark)

    Kjaergard, Lise L; Liu, Jianping; Als-Nielsen, Bodil;

    2003-01-01

    Artificial and bioartificial support systems may provide a "bridge" for patients with severe liver disease to recovery or transplantation.......Artificial and bioartificial support systems may provide a "bridge" for patients with severe liver disease to recovery or transplantation....

  19. Prognostic value of 13C-phenylalanine breath test on predicting survival in patients with chronic liver failure

    Institute of Scientific and Technical Information of China (English)

    I Gallardo-Wong; S Morán; G Rodríguez-Leal; B Casta(n)eda-Romero; R Mera; J Poo; M Uribe; M Dehesa

    2007-01-01

    AIM: To evaluate the prognostic value of percentage of 13C-phenylalanine oxidation (13C-PheOx) obtained by 13C-phenylalanine breath test (13C-PheBT) on the survival of patients with chronic liver failure.METHODS: The hepatic function was determined by standard liver blood tests and the percentage of 13C-PheOx in 118 chronic liver failure patients. The follow-up period was of 64 mo. Survival analysis was performed by the Kaplan-Meier method and variables that were significant (P < 0.10) in univariate analysis and subsequently introduced in a multivariate analysis according to the hazard model proposed by Cox.RESULTS: Forty-one patients died due to progressive liver failure during the follow-up period. The probability of survival at 12, 24, 36, 48 and 64 mo was 0.88, 0.78,0.66, 0.57 and 0.19, respectively. Multivariate analysis demonstrated that Child-Pugh classes, age, creatinine and the percentage of 13C-PheOx (HR 0.338, 95% CI:0.150-0.762, P = 0.009) were independent predictors of survival. When Child-Pugh classes were replaced by all the parameters of the score, only albumin, bilirubin,creatinine, age and the percentage of 13C-PheOx (HR 0.449, 95% CI: 0.206-0.979, P = 0.034) were found to be independent predictors of survival.CONCLUSION: Percentage of 13C-PheOx obtained by 13C-PheBT is a strong predictor of survival in patients with chronic liver disease.

  20. Prolonged Survival of Mice with Acute Liver Failure with Transplantation of Monkey Hepatocytes Cultured with an Antiapoptotic Pentapeptide V5

    OpenAIRE

    田中, 公章

    2007-01-01

    BACKGROUND: Because hepatocyte transplantation has been considered to be an attractive method to treat acute liver failure (ALF), efficient recovery of hepatocytes and maintenance of differentiated hepatocyte functions is of extreme importance. We here report the usefulness of an antiapoptotic pentapeptide V5, composed of Val-Pro-Met-Leu-Lys, in the monkey hepatocyte cultures. METHODS: We evaluated albumin production, metabolizing abilities of ammonia, lidocaine, and diazepam of monkey hepato...

  1. Porcine Adipose-Derived Mesenchymal Stem Cells Retain Their Stem Cell Characteristics and Cell Activities While Enhancing the Expression of Liver-Specific Genes after Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Chenxia Hu

    2016-01-01

    Full Text Available Acute liver failure (ALF is a kind of complicated syndrome. Furthermore, adipose-derived mesenchymal stem cells (ADMSCs can serve as a useful cell resource for autotransplantation due to their abundance and micro-invasive accessability. However, it is unknown how ALF will influence the characteristics of ADMSCs and whether ADMSCs from patients suffering from end-stage liver diseases are potential candidates for autotransplantation. This study was designed to compare various properties of ALF-derived ADMSCs with normal ADMSCs in pig models, with regard to their cellular morphology, cell proliferative ability, cell apoptosis, expression of surface antigens, mitochondrial and lysosomal activities, multilineage potency, and expression of liver-specific genes. Our results showed that ALF does not influence the stem cell characteristics and cell activities of ADMSCs. Intriguingly, the expression levels of several liver-specific genes in ALF-derived ADMSCs are higher than in normal ADMSCs. In conclusion, our findings indicate that the stem cell characteristics and cell activities of ADMSCs were not altered by ALF and these cells can serve as a new source for regenerative medicine.

  2. TAFI deficiency promotes liver damage in murine models of liver failure through defective down-regulation of hepatic inflammation

    NARCIS (Netherlands)

    Hugenholtz, Greg C. G.; Meijers, Joost C. M.; Adelmeijer, Jelle; Porte, Robert J.; Lisman, Ton

    2013-01-01

    Emerging evidence indicates that various haemostatic components can regulate the progression of liver disease. Thrombin-activatable fibrinolysis inhibitor (TAFI) possesses anti-inflammatory properties besides its anti-fibrinolytic function. Here, we investigated the contribution of TAFI to the progr

  3. Rapid liver enlargement and hepatic failure secondary to radiographic occult tumor invasion: two case reports and review of the literature

    Directory of Open Access Journals (Sweden)

    Simone Christine

    2012-11-01

    Full Text Available Abstract Introduction Unfamiliarity with certain clinical presentations, as illustrated in these cases, can lead to delayed diagnoses that in turn cause increased morbidity, prolonged hospitalization, and the need for autopsy. Case presentation In Case 1, a 63-year-old Caucasian woman presented with hepatic enlargement and insufficiency which progressed and resulted in her death over a period of less than 2 weeks. The patient underwent a detailed workup included magnetic resonance imaging and computed tomography scan of her liver, which did not reveal the source of her liver enlargement. Due to her progressive liver enlargement and insufficiency, she developed a life-threatening esophageal variceal bleeding during her hospital stay which further delayed the attainment of her diagnosis. She finally underwent a videoscopic laparotomy and liver biopsy which revealed complete replacement and filling in of the liver sinuous with Indian filing lobular breast cancer. The patient died shortly after her diagnosis and before she could be discharged. In Case 2, a 68-year-old Caucasian woman with non-small-cell lung cancer was admitted to our Oncology in-patient service with a presentation of rapid hepatic insufficiency and severe liver enlargement. Like the patient in Case 1, during her hospitalization, this patient underwent a thorough radiographic evaluation, including computed tomography and magnetic resonance imaging, to identify the source of her symptoms. Radiographic imaging showed only hepatomegaly and no discrete focal lesions. As the multiple imaging studies over a period of a week did not reveal a clear cause for her symptoms, she finally underwent an interventional radiology core biopsy which showed complete replacement of her liver with non-small-cell lung cancer. Her condition rapidly progressed due to continued liver enlargement and she died due to frank liver failure before her diagnosis was affirmed and she could be discharged. Conclusion

  4. Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors.

    Science.gov (United States)

    Rodrigues, Robim M; Sachinidis, Agapios; De Boe, Veerle; Rogiers, Vera; Vanhaecke, Tamara; De Kock, Joery

    2015-09-01

    Besides their role in the elucidation of pathogenic processes of medical and pharmacological nature, biomarkers can also be used to document specific toxicological events. Hepatic cells generated from human skin-derived precursors (hSKP-HPC) were previously shown to be a promising in vitro tool for the evaluation of drug-induced hepatotoxicity. In this study, their capacity to identify potential