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Sample records for acetaminophen-induced acute liver

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

    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.

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

    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.

  3. Immune mechanisms in acetaminophen-induced acute liver failure.

    Krenkel, Oliver; Mossanen, Jana C; Tacke, Frank

    2014-12-01

    An overdose of acetaminophen (N-acetyl-p-aminophenol, APAP), also termed paracetamol, can cause severe liver damage, ultimately leading to acute liver failure (ALF) with the need of liver transplantation. APAP is rapidly taken up from the intestine and metabolized in hepatocytes. A small fraction of the metabolized APAP forms cytotoxic mitochondrial protein adducts, leading to hepatocyte necrosis. The course of disease is not only critically influenced by dose of APAP and the initial hepatocyte damage, but also by the inflammatory response following acetaminophen-induced liver injury (AILI). As revealed by mouse models of AILI and corresponding translational studies in ALF patients, necrotic hepatocytes release danger-associated-molecular patterns (DAMPs), which are recognized by resident hepatic macrophages, Kupffer cell (KC), and neutrophils, leading to the activation of these cells. Activated hepatic macrophages release various proinflammatory cytokines, such as TNF-α or IL-1β, as well as chemokines (e.g., CCL2) thereby further enhancing inflammation and increasing the influx of immune cells, like bone-marrow derived monocytes and neutrophils. Monocytes are mainly recruited via their receptor CCR2 and aggravate inflammation. Infiltrating monocytes, however, can mature into monocyte-derived macrophages (MoMF), which are, in cooperation with neutrophils, also involved in the resolution of inflammation. Besides macrophages and neutrophils, distinct lymphocyte populations, especially γδ T cells, are also linked to the inflammatory response following an APAP overdose. Natural killer (NK), natural killer T (NKT) and T cells possibly further perpetuate inflammation in AILI. Understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression is essential to identify novel therapeutic targets for human disease. PMID:25568858

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

    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

  5. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.

    Kortsalioudaki, Christine; Taylor, Rachel M; Cheeseman, Paul; Bansal, Sanjay; Mieli-Vergani, Giorgina; Dhawan, Anil

    2008-01-01

    Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8

  6. Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

    Borlak, Jürgen; Chatterji, Bijon; Londhe, Kishor B; Watkins, Paul B

    2013-01-01

    Background Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (...

  7. Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury.

    Scheiermann, Patrick; Bachmann, Malte; Goren, Itamar; Zwissler, Bernhard; Pfeilschifter, Josef; Mühl, Heiko

    2013-04-01

    Acetaminophen (APAP, paracetamol)-induced hepatotoxicity, although treatable by timely application of N-acetylcysteine, can be fatal. Because it is among the common causes of acute liver failure in intensive care units and in light of its gradually increasing incidence, the need for novel therapeutic strategies aimed at severe intoxication is apparent. Recently, it has been shown that IL-22, a STAT3-activating cytokine, has the capability to mediate liver protection. Herein, the protective potential of IL-22 in murine APAP-induced hepatotoxicity was assessed. Intravenous administration of prophylactic IL-22 significantly reduced serum alanine aminotransferase levels and histopathologic damage in APAP-induced liver injury, a process that coincided with increased hepatocyte proliferation in vivo. Concomitant gene expression analysis revealed hepatic induction of genes prototypically up-regulated by the IL-22/STAT3 axis, among others suppressor of cytokine signaling-3, lipocalin-2, and α1-antichymotrypsin. Notably, in a translational setting of therapeutic treatment 2 hours after APAP, IL-22 supported protection in the context of suboptimal N-acetylcysteine dosing. IL-22 likewise connected to augmented hepatocyte proliferation in this experimental setting. As detected by analysis of inflammatory cytokine production, systemically applied IL-22 did not display acute immunomodulation/stimulation in otherwise untreated or endotoxemic mice. Those latter observations clearly confirm acute tolerability of systemically applied IL-22. Observations presented altogether suggest that therapeutic IL-22 administration is a conceivable tissue-protective regimen aimed at hard-to-treat patients with severe APAP-induced hepatotoxicity. PMID:23375450

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

    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.

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

    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 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...

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

    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 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 necr...

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

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

    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 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 (pintoxication 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. PMID:23166697

  13. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis.

    Yan, Tingting; Wang, Hong; Zhao, Min; Yagai, Tomoki; Chai, Yingying; Krausz, Kristopher W; Xie, Cen; Cheng, Xuefang; Zhang, Jun; Che, Yuan; Li, Feiyan; Wu, Yuzheng; Brocker, Chad N; Gonzalez, Frank J; Wang, Guangji; Hao, Haiping

    2016-05-01

    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID:26965985

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

    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. Protective effects from Houttuynia cordata aqueous extract against acetaminophen-induced liver injury

    Chen, Wei-Ting; Yang, Chieh-ling; Yin, Mei-chin

    2014-01-01

    Background Protective effects of Houttuynia cordata aqueous extract (HCAE) against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. Methods HCAE, at 1 or 2 g/L, was added into the drinking water for 4 weeks. Acute liver injury was induced by acetaminophen treatment intraperitoneally (350 mg/kg body weight). Results Acetaminophen treatment significantly depleted hepatic glutathione (GSH) content, increased hepatic malonyldialdehyde (MDA), reactive oxygen species (ROS) and ox...

  16. Protective effect of naringenin against acetaminophen-induced acute liver injury in metallothionein (MT)-null mice.

    Lv, Yingjian; Zhang, Baoxu; Xing, Guozhen; Wang, Fuqiang; Hu, Zhewen

    2013-02-01

    Naringenin is a natural flavonoid aglycone of naringin that has been reported to have a wide range of pharmacological properties, such as antioxidant activity and free radical scavenging capacity. This study was designed to examine the hepatoprotective effect of naringenin against acetaminophen (250 mg kg(-1), sc) in metallothionein (MT)-null mice. 42 SPF MT-knockout mice were used. Naringenin (200, 400, and 800 mg kg(-1), ig) was administered for 4 days before exposure to acetaminophen (250 mg kg(-1), sc). Liver injury was measured by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as liver malondialdehyde (MDA). The glutathione-to-oxidized glutathione ratio (GSH/GSSG) was also assessed. The evidence of liver injury induced by acetaminophen included not only a significant increase in the levels of serum ALT, AST, LDH and liver MDA, and also a significant decrease in GSH/GSSG. Pretreatment of mice with naringenin at 400 and 800 mg kg(-1) reversed the altered parameters. Such reversal effects were dose-dependent: ALT decreased 78.62% and 98.03%, AST decreased 88.35% and 92.64%, LDH decreased 76.54% and 81.63%, MDA decreased 48.59% and 66.27% at a dose of 400 and 800 mg kg(-1) respectively; GSH/GSSG increased 22.57% and 16.93% at a dose of 400 and 800 mg kg(-1) respectively. Histopathological observation findings were also consistent with these effects. Together, this study suggests that naringenin can potentially reverse the hepatotoxic damage of acetaminophen intoxication in MT-null mice. PMID:23142768

  17. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2α and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

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

    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.

  19. Acetaminophen-Induced Acute Pancreatitis. A Case Report

    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.

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

    Maria Goretti R. Queiroz; José Henrique L. Cardoso; Adriana R. Tomé; 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

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

    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].

  2. Role of nicotinamide (vitamin B3) in acetaminophen-induced changes in rat liver: Nicotinamide effect in acetaminophen-damged liver.

    Mahmoud, Yomna I; Mahmoud, Asmaa A

    2016-06-01

    Acetaminophen is a widely used analgesic and antipyretic agent, which is safe at therapeutic doses. However, overdoses of acetaminophen induce severe oxidative stress, which leads to acute liver failure. Nicotinamide has proven effective in ameliorating many pathological conditions that occur due to oxidative stress. This study verifies the prophylactic and therapeutic effects of nicotinamide against the hepatic pathophysiological and ultrastructural alterations induced by acetaminophen. Wistar rats intoxicated with an acute overdose of acetaminophen (5g/kg b.wt) were given a single dose of nicotinamide (500mg/kg b.wt) either before or after intoxication. Acetaminophen caused significant elevation in the liver functions and lipid peroxidation marker, and decline in the activities of the hepatic antioxidant enzymes. This oxidative injury was associated with hepatic centrilobular necrosis, hemorrage, vacuolar degeneration, lipid accumulation and mitochondrial alterations. Treating intoxicated rats with nicotinamide (500mg/kg) significantly ameliorated acetaminophen-induced biochemical changes and pathological injuries. However, administering the same dose of nicotinamide to healthy animals or prior to acetaminophen-intoxication induced hepatotoxicity. Caution should be taken when administering high doses of NAM because of its possible hepatotoxicity. Considering the wide use of nicotinamide, there is an important need for monitoring nicotinamide tolerance, safety and efficacy in healthy and diseased subjects. PMID:27211843

  3. Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

    Roko Martinić

    2014-08-01

    Full Text Available Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for several different animal disease models. In this group plasma alanine aminotransferase and aspartate aminotransferase enzyme activities, as well as liver necrosis score were significantly reduced in comparison to control animals treated with physiological saline (p > 0.01. The specificity of the peptide hepatoprotection was investigated from the standpoint of the receptor and peptide blockade. It was concluded that Met-enkephalin effects on the liver were mediated via δ and ζ opioid receptors. Genotoxic testing of Met-enkephalin confirmed the safety of the peptide.

  4. Pathogenic Role of NKT and NK Cells in Acetaminophen-Induced Liver Injury is Dependent on the Presence of DMSO

    Masson, Mary Jane; Carpenter, Leah D.; Graf, Mary L.; Pohl, Lance R.

    2008-01-01

    Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. While DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked. An example highlighting this potential problem is found in the recent report demonstrating a pathogenic role for NKT and NK cells in acetaminophen-induced liver injury (AILI) in C57Bl/6 mice in which DMSO was used to facilitate APAP dissolution. We ...

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

    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

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

    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

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

    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

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

    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.

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

    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.

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

    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

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

    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

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

    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.

  13. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

  14. The therapeutic detoxification of chlorogenic acid against acetaminophen-induced liver injury by ameliorating hepatic inflammation.

    Zheng, Zhiyong; Sheng, Yuchen; Lu, Bing; Ji, Lili

    2015-08-01

    Chlorogenic acid (CGA) has been reported to prevent acetaminophen (AP)-induced hepatotoxicity when mice were pre-administered orally with CGA for consecutive 7days before AP intoxication in our previous study. This study investigated the therapeutic detoxification of CGA against AP-induced hepatotoxicity and the engaged mechanism. The mice were orally administered with CGA (10, 20, 40mg/kg) at 1h after given AP (400mg/kg), and another 3h later the mice were killed for the following experiments. Results of serum transaminases analysis and histological evaluation demonstrated the detoxification of CGA against AP-induced hepatotoxicity. CGA reduced AP-induced the increased myeloperoxidase (MPO) enzymatic activity and its expression. CGA reduced AP-induced the increased liver expression of toll-like receptor (TLR)-3/4 and MyD88, and the increased phosphorylation of inhibitor of kappa B (IκB) and p65 subunit of nuclear factor κB (NFκB). CGA reduced AP-induced the increased NFκBp65 expression in nucleus. In addition, CGA reduced AP-induced the increased serum levels and liver mRNA expression of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), and keratinocyte chemoattractant (KC). Taken together, our results demonstrate the therapeutic detoxification of CGA against AP-induced liver injury, and TLR3/4 and NFκB signaling pathway are involved in such process. PMID:26079055

  15. Protective effects of (-)-epigallocatechin-3-gallate against acetaminophen-induced liver injury in rats)

    Yao, Hsien-Tsung; Yang, Yu-Chi; Chang, Chen-Hui; Yang, Hui-Ting; Yin, Mei-chin

    2015-01-01

    (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin with various biological activities found in tea. In this study, the effects of EGCG on the metabolism and toxicity of acetaminophen in rat liver were investigated. Male Sprague-Dawley rats were fed a controlled diet without or with EGCG (0.54 %, w/w) for 1 week and were then intraperitoneally injected with acetaminophen (1 g/kg body weight) and killed after 12 h. Concentrations of acetaminophen and its conjugates in plasma an...

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

    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.

  17. Acetaminophen-induced microvascular injury in the rat liver: protection with misoprostol.

    Lim, S P; Andrews, F J; O'Brien, P E

    1995-12-01

    Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mg/kg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin E1 analog) treatment (6 x 25 micrograms/kg) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with APAP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level. PMID:7489988

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

    Ndatsu Yakubu; Umaru Alhassan Mohammed

    2016-01-01

    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 investigate...

  19. 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

    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.

  20. Acetaminophen induced nephrotoxicity in an adolescent girl

    Belde; Mehmet; Demet; Alper; Salih

    2011-01-01

    Acetaminophen induced nephrotoxicity is not a frequent consequence of acetaminophen overdose. The pathophysiology has been attributed to oxidative stress. Here, we report a 16-year-old female patient who developed non-oliguric acute renal failure without hepatotoxicity following ingestion of 14 tablets of 500 mg acetaminophen and recovered spontaneously in a week. (Turk Arch Ped 2011; 46: 343-5)

  1. Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

    Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI. When male C57BL/6J wild type (WT) and JNK2-/- mice were treated with 300 mg APAP/kg, 90% of JNK2-/- mice died of ALF compared to 20% of WT mice within 48 h. The high susceptibility of JNK2-/- mice to AILI appears to be due in part to deficiencies in hepatocyte proliferation and repair. Therefore, our findings are consistent with JNK2 signaling playing a protective role in AILI and further suggest that the use of JNK inhibitors as a potential treatment for AILI, as has been recommended by other investigators, should be reconsidered

  2. The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c.2042C>G (rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant mRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver FailureS⃞

    Court, Michael H; Freytsis, Marina; Wang, Xueding; Peter, Inga; Guillemette, Chantal; Hazarika, Suwagmani; Duan, Su X.; Greenblatt, David J; Lee, William M.

    2013-01-01

    Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of th...

  3. Effects of Hepatoprotective Compounds from the Leaves of Lumnitzera racemosa on Acetaminophen-Induced Liver Damage in Vitro.

    Darwish, Ahmed Gomaa Gomaa; Samy, Mamdouh Nabil; Sugimoto, Sachiko; Otsuka, Hideaki; Abdel-Salam, Hosni; Matsunami, Katsuyoshi

    2016-01-01

    Phytochemical investigation of the n-BuOH fraction of the mangrove plant Lumnitzera racemosa WILLD. (Combretaceae) led to the isolation of one new flavonoid glycoside; myrcetin 3-O-methyl glucuronate (1), one new phenolic glycoside; lumniracemoside (2) and one new aliphatic alcohol glycoside; n-hexanol 1-O-rutinoside (3), in addition to seven known compounds (4-10). The structures of these compounds were determined by spectroscopic analyses (UV, IR, high resolution-electrospray ionization (HR-ESI)-MS, one- and two-dimensional (1D- and 2D)-NMR). Compound 7 showed the highest hepatoprotective activity against acetaminophen-induced hepatotoxicity using human HepG2 cells at protection % value of 34.2±3.1%, while compounds 1, 2, 3, 6, and 9 showed weak to moderate hepatoprotective activity (11.6-18.9%). Almost all of these compounds showed stronger 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity compared with the standard Trolox. These results suggest the usefulness of this plant extract and the isolated compounds as promising hepatoprotective agents. PMID:27039833

  4. Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis.

    Rizvi, Fatima; Mathur, Alpana; Kakkar, Poonam

    2015-10-01

    Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI. PMID:26286854

  5. Role of caspase-1 and interleukin-1β in acetaminophen-induced hepatic inflammation and liver injury

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1β signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1β formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1β during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1β gene transcription but prevented the increase in IL-1β plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1β to increase injury, mice were given pharmacological doses of IL-1β after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1β formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1β, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.

  6. Effect of Conditioned Medium and Bone Marrow Stem Cell Lysate on the Course of Acetaminophen-Induced Liver Failure.

    Khubutiya, M Sh; Temnov, A A; Vagabov, V A; Sklifas, A N; Rogov, K A; Zhgutov, Yu A

    2015-05-01

    A composition containing culture medium conditioned by mesenchymal stem cells and mesenchymal stem cell lysate improves biochemical parameters, reduces inflammation, and stimulates regenerative processes in the liver. PMID:26033600

  7. Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury

    Patrick Scheiermann; Malte Bachmann; Lorena Härdle; Thomas Pleli; Albrecht Piiper; Bernhard Zwissler; Josef Pfeilschifter; Heiko Mühl

    2015-01-01

    Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36γ has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36γ in acute liver disease focusing o...

  8. Liver autophagy in anorexia nervosa and acute liver injury.

    Kheloufi, Marouane; Boulanger, Chantal M; Durand, François; Rautou, Pierre-Emmanuel

    2014-01-01

    Autophagy, a lysosomal catabolic pathway for long-lived proteins and damaged organelles, is crucial for cell homeostasis, and survival under stressful conditions. During starvation, autophagy is induced in numerous organisms ranging from yeast to mammals, and promotes survival by supplying nutrients and energy. In the early neonatal period, when transplacental nutrients supply is interrupted, starvation-induced autophagy is crucial for neonates' survival. In adult animals, autophagy provides amino acids and participates in glucose metabolism following starvation. In patients with anorexia nervosa, autophagy appears initially protective, allowing cells to copes with nutrient deprivation. However, when starvation is critically prolonged and when body mass index reaches 13 kg/m(2) or lower, acute liver insufficiency occurs with features of autophagic cell death, which can be observed by electron microscopy analysis of liver biopsy samples. In acetaminophen overdose, a classic cause of severe liver injury, autophagy is induced as a protective mechanism. Pharmacological enhancement of autophagy protects against acetaminophen-induced necrosis. Autophagy is also activated as a rescue mechanism in response to Efavirenz-induced mitochondrial dysfunction. However, Efavirenz overdose blocks autophagy leading to liver cell death. In conclusion, in acute liver injury, autophagy appears as a protective mechanism that can be however blocked or overwhelmed. PMID:25250330

  9. Liver Autophagy in Anorexia Nervosa and Acute Liver Injury

    Marouane Kheloufi

    2014-01-01

    Full Text Available Autophagy, a lysosomal catabolic pathway for long-lived proteins and damaged organelles, is crucial for cell homeostasis, and survival under stressful conditions. During starvation, autophagy is induced in numerous organisms ranging from yeast to mammals, and promotes survival by supplying nutrients and energy. In the early neonatal period, when transplacental nutrients supply is interrupted, starvation-induced autophagy is crucial for neonates’ survival. In adult animals, autophagy provides amino acids and participates in glucose metabolism following starvation. In patients with anorexia nervosa, autophagy appears initially protective, allowing cells to copes with nutrient deprivation. However, when starvation is critically prolonged and when body mass index reaches 13 kg/m2 or lower, acute liver insufficiency occurs with features of autophagic cell death, which can be observed by electron microscopy analysis of liver biopsy samples. In acetaminophen overdose, a classic cause of severe liver injury, autophagy is induced as a protective mechanism. Pharmacological enhancement of autophagy protects against acetaminophen-induced necrosis. Autophagy is also activated as a rescue mechanism in response to Efavirenz-induced mitochondrial dysfunction. However, Efavirenz overdose blocks autophagy leading to liver cell death. In conclusion, in acute liver injury, autophagy appears as a protective mechanism that can be however blocked or overwhelmed.

  10. Acetaminophen-induced Liver Injury in Rats and Mice: Comparison of Protein Adducts, Mitochondrial Dysfunction, and Oxidative Stress in the Mechanism of Toxicity

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

    2012-01-01

    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 toxi...

  11. Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury.

    Scheiermann, Patrick; Bachmann, Malte; Härdle, Lorena; Pleli, Thomas; Piiper, Albrecht; Zwissler, Bernhard; Pfeilschifter, Josef; Mühl, Heiko

    2015-01-01

    Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36γ has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36γ in acute liver disease focusing on murine APAP-induced hepatotoxicity. Enhanced expression of hepatic IL-36γ and its prime downstream chemokine target CCL20 was detected upon liver injury. CCL20 expression coincided with the later regeneration phase of intoxication. Primary murine hepatocytes and human Huh7 hepatocellular carcinoma cells indeed displayed enhanced IL-36γ expression when exposed to inflammatory cytokines. Administration of IL-36 receptor antagonist (IL-36Ra) decreased hepatic CCL20 in APAP-treated mice. Unexpectedly, IL-36Ra likewise increased late phase hepatic injury as detected by augmented serum alanine aminotransferase activity and histological necrosis which suggests disturbed tissue recovery upon IL-36 blockage. Finally, we demonstrate induction of IL-36γ in inflamed livers of endotoxemic mice. Observations presented introduce IL-36γ as novel parameter in acute liver injury which may contribute to the decision between unleashed tissue damage and initiation of liver regeneration during late APAP toxicity. PMID:25687687

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

    Kannan, Narayanan; Sakthivel, Kunnathur Murugesan; Guruvayoorappan, Chandrasekaran

    2013-01-01

    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, ...

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

    Farida Yesmin; Zaida Rahman; Jesmin Fouzia Dewan; Asadul Mazid Helali; Md Zakirul Islam; Rahman, Nor Iza A; Tengku Fatimah Murniwati Binti Tengku Muda; Mainul Haque

    2013-01-01

    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 oral...

  14. Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

    Mazer, Maryann; Perrone, Jeanmarie

    2008-01-01

    Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1–2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the ro...

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

    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

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

    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

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

    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. PMID:22980195

  18. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1-/-) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1-/- mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1-/- mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1-/- mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1-/- mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

  19. Plasma glutathione S-transferase and F protein are more sensitive than alanine aminotransferase as markers of paracetamol (acetaminophen)-induced liver damage.

    Beckett, G J; Foster, G R; Hussey, A J; Oliveira, D B; Donovan, J W; Prescott, L F; Proudfoot, A T

    1989-11-01

    Concentrations of glutathione S-transferase (GST; glutathione transferase; EC 2.5.1.18) B1 subunits, F protein, and the activity of alanine aminotransferase (ALT; EC 2.6.1.2) were measured in sequential plasma samples taken from nine patients with self-administered paracetamol (acetaminophen) poisoning. GST exceeded the reference interval in all patients at the time of admission, and F protein was increased in seven. In contrast, abnormal activities of ALT in plasma were found in only one of the nine on admission, a patient admitted 12 h after poisoning. Subsequent to admission nine, eight, and five patients, respectively, had abnormal concentrations of GST, F protein, and ALT. When expressed as multiples of the upper reference limit, the highest values for GST measured in each patient always far exceeded the greatest abnormalities in ALT; this was true for F protein in only five patients. Patients in whom the concentration of GST exceeded 10 micrograms/L on admission subsequently went on to develop moderate or severe liver damage, despite treatment with N-acetylcysteine. F protein and ALT measurements on admission were not as efficient as GST at predicting the clinical outcome of the patients. We conclude that GST and F protein offer clear advantages over ALT for detecting minor degrees of acute liver dysfunction, particularly when only centrilobular damage may be involved. PMID:2582614

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

    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...... sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39...

  1. Acute liver failure

    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....

  2. 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

    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

  3. Effects of the Total Saponins from Rosa laevigata Michx Fruit against Acetaminophen-Induced Liver Damage in Mice via Induction of Autophagy and Suppression of Inflammation and Apoptosis

    Deshi Dong

    2014-05-01

    Full Text Available The effect of the total saponins from Rosa laevigata Michx fruit (RLTS against acetaminophen (APAP-induced liver damage in mice was evaluated in the present paper. The results showed that RLTS markedly improved the levels of liver SOD, CAT, GSH, GSH-Px, MDA, NO and iNOS, and the activities of serum ALT and AST caused by APAP. Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT-mediated dUTP nick end labeling (TUNEL and transmission electron microscopy (TEM assays. In addition, RLTS decreased the gene or protein expressions of cytochrome P450 (CYP2E1, pro-inflammatory mediators (IL-1β, IL-4, IL-6, TNF-α, iNOS, Bax, HMGB-1 and COX-2, pro-inflammatory transcription factors (NF-κB and AP-1, pro-apoptotic proteins (cytochrome C, p53, caspase-3, caspase-9, p-JNK, p-p38 and p-ERK, and increased the protein expressions of Bcl-2 and Bcl-xL. Moreover, the gene expression of IL-10, and the proteins including LC3, Beclin-1 and Atg5 induced by APAP were even more augmented by the extract. These results demonstrate that RLTS has hepatoprotective effects through antioxidative action, induction of autophagy, and suppression of inflammation and apoptosis, and could be developed as a potential candidate to treat APAP-induced liver damage in the future.

  4. Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation

    The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells

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

    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.

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

    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

  7. Hepatoprotective and anti-oxidant activities of Glossogyne tenuifolia against acetaminophen-induced hepatotoxicity in mice.

    Tien, Yu-Hsiu; Chen, Bing-Huei; Wang Hsu, Guoo-Shyng; Lin, Wan-Teng; Huang, Jui-Hua; Lu, Yi-Fa

    2014-01-01

    The present study investigated the anti-oxidative and hepatoprotective effects of Glossogyne tenuifolia (GT) Cassini, against acetaminophen-induced acute liver injury in BALB/c mice. The extracts of GT by various solvents (hot water, 50% ethanol and 95% ethanol) were compared for their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power, total phenolic content, and total anti-oxidant capacity. The results showed that hot water (HW) extracts of GT contained high levels of phenolics and exerted an excellent anti-oxidative capacity; thus, these were used in the animal experiment. The male BALB/c mice were randomly divided into control group, acetaminophen (APAP) group, positive control group and two GT groups at low (GT-L) and high (GT-H) dosages. The results showed that mice treated with GT had significantly decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). GT-H increased glutathione levels and the ratios of reduced glutathione and oxidized glutathione (GSH/GSSG) in the liver, and inhibited serum and lipid peroxidation. This experiment was the first to determine phenolic compounds, chlorogenic acid and luteolin-7-glucoside in HW extract of GT. In conclusion, HW extract of GT may have potential anti-oxidant capacity and show hepatoprotective capacities in APAP-induced liver damaged mice. PMID:25384447

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

    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.

  9. Hepatoprotective activity of Centaurium erythraea on acetaminophen-induced hepatotoxicity in rats.

    Mroueh, Mohamad; Saab, Yolande; Rizkallah, Raed

    2004-05-01

    The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for hepatoprotective activity against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). The activity of the extract was supported by histopathological examination of liver sections. PMID:15174008

  10. Acute liver failure

    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...... transplantation (ELT) is an established treatment option. These improvements in care are such that the majority of patients may now be expected to survive (Fig. 1). Key features of the condition have changed dramatically over time, with a remarkable fall in the incidence of cerebral edema and intracranial...

  11. Effect of Methylsulfonylmethane Pretreatment on Aceta-minophen Induced Hepatotoxicity in Rats

    Shahab Bohlooli; Sadollah Mohammadi; Keyvan Amirshahrokhi; Hafez Mirzanejad-asl; Mohammad Yosefi; Amir Mohammadi-Nei; Mir Mehdi Chinifroush

    2013-01-01

    Objective(s): Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains and beverages. In this study the effect of MSM pretreatment on acetaminophen induced liver damage was investigated. Materials and Methods: Male Sprague Dawley rats were pretreated with 100 mg/kg MSM for one week. On day seven rats were received acetaminophen (850 mg/kg, intraperitoneal). Twenty-four hours later, blood samples were taken to determi...

  12. Protective effect of zinc aspartate against acetaminophen induced hepato-renal toxicity in albino rats

    Zinc is an essential nutrient that is required in humans and animals for many physiological functions, including antioxidant functions. The evidence to date indicates that zinc is an important element that links antioxidant system and tissue damage. Acetaminophen (AP), a widely used analgesic and antipyretic, produces hepatocyte and renal tubular necrosis in human and animals following overdose. In human, AP is one of the most common causes of acute liver failure as a result of accidental or deliberate overdose. Moreover, the initial event in AP toxicity is a toxic metabolic injury with the release of free radicals and subsequent cellular death by necrosis and apoptosis. This study was designed to evaluate the potential protective role of zinc aspartate in case of acetaminophen induced hepato-renal toxicity in rats. A total number of 32 adult male albino rats were divided into 4 equal groups: group I (control group), group II (zinc aspartate treated group), group III (acetaminophen treated group; by a single oral dose of 750 mg/kg body weight) and group IV acetaminophen plus zinc treated group; (zinc aspartate was intraperitoneally given one hour after acetaminophen administration in a dose of 30 mg/kg body weight). Serum levels of: alanine aminotransferase, aspartate aminotransferase, direct bilirubin, blood urea nitrogen, creatinine, uric acid, xanthine oxidase (XO), glutathione (GSH), malonaldehyde (MDA) and nitric oxide (NO) were assessed in all groups. The results of this study showed that treatment with acetaminophen alone (group III) produced a significant increase in serum levels of the liver enzymes and direct bilirubin. Moreover, in the same group there was a significant increase in the blood urea nitrogen and serum creatinine compared to the control group. In addition, there was a significant increase in XO and MDA and a significant decrease in GSH and NO level. Injection of rats with zinc aspartate after acetaminophen treatment could produce a

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

    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.

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

    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...

  15. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update.

    Yoon, Eric; Babar, Arooj; Choudhary, Moaz; Kutner, Matthew; Pyrsopoulos, Nikolaos

    2016-06-28

    Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways. PMID:27350943

  16. Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis, oxidative stress and inflammation.

    Zhang, Weixin; Yin, Lianhong; Tao, Xufeng; Xu, Lina; Zheng, Lingli; Han, Xu; Xu, Youwei; Wang, Changyuan; Peng, Jinyong

    2016-07-01

    In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future. PMID:27317992

  17. Acute liver failure and liver transplantation.

    Akamatsu, Nobuhisa; Sugawara, Yasuhiko; Kokudo, Norihiro

    2013-08-01

    Acute liver failure (ALF) is defined by the presence of coagulopathy (International Normalized Ratio ≥ 1.5) and hepatic encephalopathy due to severe liver damage in patients without pre-existing liver disease. Although the mortality due to ALF without liver transplantation is over 80%, the survival rates of patients have considerably improved with the advent of liver transplantation, up to 60% to 90% in the last two decades. Recent large studies in Western countries reported 1, 5, and 10-year patient survival rates after liver transplantation for ALF of approximately 80%, 70%, and 65%, respectively. Living donor liver transplantation (LDLT), which has mainly evolved in Asian countries where organ availability from deceased donors is extremely scarce, has also improved the survival rate of ALF patients in these regions. According to recent reports, the overall survival rate of adult ALF patients who underwent LDLT ranges from 60% to 90%. Although there is still controversy regarding the graft type, optimal graft volume, and ethical issues, LDLT has become an established treatment option for ALF in areas where the use of deceased donor organs is severely restricted. PMID:25343108

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

    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.

  19. Spathodea campanulata Extract Attenuates Acetaminophen-Induced Hepatic Injury in Mice

    Phyllis Elsie Dadzeasah

    2013-10-01

    Full Text Available Spathodea campanulata, well known for its traditional medicinal uses was investigated for hepatoprotective activity against acetaminophen-induced hepatic damage in mice. Six groups of mice were pre-treated with 100, 300 and 625 mg/kg of the aqueous extract of Spathodea campanulata stem bark, N-acetyl cysteine (300 mg/kg; p.o or distilled water for 5 days before they were intoxicated with a single dose of acetaminophen (600 mg/kg; p.o. Alanine aminotransferase, Aspartate aminotransferase and total protein levels were measured in serum, glutathione peroxidase, superoxide dismutase and total cytochrome P450 levels were measured in liver homogenate and liver histology was also observed on liver sections. Total liver cytochrome P450 levels in Spathodea campanulata extract, distilled water, ketoconazole or phenobarbital-treated animals were also measured. Significant hepatoprotection was obtained against liver damage induced by acetaminophen as evident from decreased serum levels of Aspartate transaminase, Alanine transaminase and increased levels of total protein in the combined acetaminophen and extract treated groups and the acetaminophen and N-acetylcysteine-treated groups compared to the acetaminophen only controls. The decrease in serum antioxidant enzymes; glutathione peroxidase and superoxide dismutase levels caused by acetaminophen was significantly reversed by the extract. The results correlated well with the histopathology of liver from treated and control animals. The extract also caused considerable inhibition of total CYP450, the enzymes involved in the activation of acetaminophen. The present results indicate that Spathodea campanulata protects the liver against acetaminophen-induced hepatotoxicity by enhancing antioxidant protection capacity and interfering with the bio-activation of acetaminophen.

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

    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. PMID:21975853

  1. Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice

    Hepatocyte proliferation represents an important part of tissue repair. In these studies, TNF receptor 1 (TNFR1) knockout mice were used to analyze the role of TNF-α in hepatocyte proliferation during acetaminophen-induced hepatotoxicity. Treatment of wild-type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was associated with proliferation of hepatocytes surrounding the damaged areas, which was evident at 24 h. The cell cycle regulatory proteins, cyclin D1 and cyclin A, were also up regulated in hepatocytes. In contrast, in TNFR1-/- mice, which exhibit exaggerated acetaminophen hepatotoxicity, hepatocyte proliferation, and expression of cyclin D1 and cyclin A, as well as the cyclin dependent kinases, Cdk4 and Cdk2, were reduced. The cyclin-dependent kinase inhibitor p21 was also induced in the liver following acetaminophen administration. This was greater in TNFR1-/- mice compared to WT mice. To investigate mechanisms mediating the reduced hepatic proliferative response of TNFR1-/- mice, we analyzed phosphatidyl inositol-3-kinase (PI-3K) signaling. In both WT and TNFR1-/- mice, acetaminophen caused a rapid increase in total PI-3K within 3 h. Acetaminophen also increased phosphorylated PI-3K, but this was delayed 6-12 h in TNFR1-/- mice. Expression of Akt, a downstream target of PI-3K, was increased in both WT and TNFR1-/- mice in response to acetaminophen. However, the increase was greater in WT mice. Acetaminophen-induced expression of phosphorylated STAT3, a key regulator of cytokine-induced hepatocyte proliferation, was also delayed in TNFR1-/- mice relative to WT. These data suggest that TNF-α signaling through TNFR1 is important in regulating hepatocyte proliferation following acetaminophen-induced tissue injury. Delayed cytokine signaling may account for reduced hepatocyte proliferation and contribute to exaggerated acetaminophen-induced hepatotoxicity in TNFR1-/- mice

  2. Micro-RNA-122 Levels in Acute Liver Failure and Chronic Hepatitis C

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

    2016-01-01

    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. PMID:24895202

  3. Acute liver failure and self-medication

    de OLIVEIRA, André Vitorio Câmara; ROCHA, Frederico Theobaldo Ramos; ABREU, Sílvio Romero de Oliveira

    2014-01-01

    Introduction 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. Aim To warn about how the practice of self-medication can be responsible for acute liver failure. Method Were used the Medline via PubMed, Cochrane Library, SciELO and Lilacs, and additional information on institutional sites of interest crossing the headings acute live...

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

    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.

  5. The Pathology of Acute Liver Failure.

    Lefkowitch, Jay H

    2016-05-01

    Acute liver failure (ALF) is a rare and severe liver disease that usually develops in 8 weeks or less in individuals without preexisting liver disease. Its chief causes worldwide are hepatitis virus infections (hepatitis A, B, and E) and drug hepatotoxicity (particularly intentional or unintentional acetaminophen toxicity). Massive hepatic necrosis is often seen in liver specimens in ALF and features marked loss of hepatocytes, variable degrees of inflammation, and a stereotypic proliferation of bile ductular structures (neocholangioles) derived from activated periportal hepatic progenitor cells. This paper reviews the liver pathology in ALF, including forms of zonal necrosis and their etiologies. PMID:27058243

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

    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.

  7. Clinical heterogeneity in autoimmune acute liver failure

    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.

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

    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.

  9. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice.

    Barman, P K; Mukherjee, R; Prusty, B K; Suklabaidya, S; Senapati, S; Ravindran, B

    2016-01-01

    Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1β as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1β and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1β in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose. PMID:27171266

  10. Acute alcohol-induced liver injury

    Gavin Edward Arteel

    2012-06-01

    Full Text Available Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, that also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

  11. Acute myopathy associated with liver cirrhosis

    Ok-Jae Lee; Jee-Hyang Yoon; Eun-Jeong Lee; Hyun-Jin Kim; Tae-Hyo Kim

    2006-01-01

    AIM: Many cirrhotic patients have muscular symptoms and rhabdomyolysis. However, myopathy associated with liver cirrhosis has not been established as a disease entity. We evaluated the clinical significance of acute myopathy associated with liver cirrhosis.METHODS: We retrospectively reviewed the medical records of 5440 cirrhotic patients who had been admitted to Gyeongsang National University Hospital from August 1997 to January 2003. Among these, 99 developed acute myopathies, and they were analyzed with respect to clinical and laboratory parameters, and outcomes.RESULTS: The Child-Pugh classification at the time of myopathy onset was A in 3(3.1%) cases, B in 33(33.3%), and C in 63 (63.6%). Infection was identified as the most predisposing factor to myopathy. Fifty percent of 18 idiopathic cases who were tested for influenza antibody were positive. Forty-two of the 99 cases were complicated by acute renal failure, and 25 (59.5%) of these expired. Apart from 6 cases lost to follow-up, 64 of 93 recovered, giving a mortality rate of 31.2%. Mortality was higher in Child-Pugh class C than in B or A.CONCLUSION: Acute myopathy can develop as a serious complication in liver cirrhosis. Its frequency, severity and mortality depend on underlying liver function, and are higher in decompensated liver cirrhosis. Influenza should be considered as an etiologic factor in idiopathic cases. It is proposed that acute myopathy associated with liver cirrhosis be called 'hepatic myopathy', and that careful monitoring for hepatic myopathy is necessary in the patients with advanced liver cirrhosis.

  12. Dengue fever with acute liver failure

    Vinodh B

    2005-01-01

    Full Text Available A virus belonging to the Flaviviridae group causes dengue haemorrhagic fever. Dengue presenting as acute liver failure is rare. Dengue is endemic in India. The last epidemic of dengue occurred in Delhi in 2003. During this epidemic, 2185 confirmed cases of dengue were reported. Dengue virus serotypes 2 and 3 were responsible for this epidemic. A 19-yr-old male presented to our hospital with the complaints of fever for 12 days, during this epidemic. He was diagnosed as having dengue shock syndrome, stage IV with acute liver failure. He had primary dengue infection. He made complete recovery with supportive management.

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

    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.

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

    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

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

    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).

  16. Therapeutic hypothermia for acute liver failure

    Stravitz, R.T.; Larsen, Finn Stolze

    2009-01-01

    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...... 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...

  17. Portal hypertension in acute liver failure.

    3.M. Navasa; Garcia-Pagán, J C; Bosch, J; Riera, J R; R. Bañares; Mas, A.; Bruguera, M; Rodés, J

    1992-01-01

    Twenty five patients with acute liver failure were measured for hepatic venous pressure gradient as an index of portal pressure during the course of a transjugular liver biopsy. Hepatic venous pressure gradient ranged from 4 to 24.5 mm Hg with a mean of 12.8 (5.3) mm Hg (normal values less than 5 mm Hg). All patients but one had increased portal pressure gradient. Portal hypertension correlated with the degree of architectural distortion of the liver, as suggested by a direct correlation betw...

  18. Lethal acute liver failure in a patient treated with sunitinib.

    Guillen, S S; Meijer, M; de Jongh, F E

    2016-01-01

    Sunitinib is a tyrosine kinase inhibitor that is used as an anticancer drug in renal cell carcinoma (RCC), pancreatic neuroendocrine tumours (PNETs) and gastrointestinal stromal tumour. Elevated liver enzymes are frequently observed during treatment but acute liver failure is uncommon. We describe a case of fulminant acute liver failure and acute kidney injury during treatment with sunitinib for metastatic RCC. PMID:26933184

  19. Plasma osteopontin in acute liver failure

    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...... and 3 days after undergoing spine fusion (SF) surgery as a model for acute inflammation. RESULTS: Median plasma OPN levels across all etiologies of ALF patients were elevated 10- to 30-fold: overall median 1055ng/mL; range: 33-19,127), when compared to healthy controls (median in pre-SF patients: 41ng...

  20. ACUTE APENDICITIS IN LIVER TRANSPLANT RECIPIENTS

    da FONSECA-NETO, Olival Cirilo Lucena; LIMA, Heloise Caroline de Souza; de MELO, Paulo Sérgio Vieira; LEMOS, Roberto; LEITÃO, Laércio; AMORIM, Américo Gusmão; LACERDA, Cláudio Moura

    2016-01-01

    Background : Appendicitis is a common cause of emergency surgery that in the population undergoing organ transplantation presents a rare incidence due to late diagnosis and treatment. Aim : To report the occurrence of acute appendicitis in a cohort of liver transplant recipients. Methods : Retrospective analysis in a period of 12 years among 925 liver transplants, in witch five cases of acute appendicitis were encountered. Results : Appendicitis occurred between three and 46 months after liver transplantation. The age ranged between 15 and 58 years. There were three men and two women. The clinical presentations varied, but not discordant from those found in non-transplanted patients. Pain was a symptom found in all patients, in two cases well located in the right iliac fossa (40%). Two patients had symptoms characteristic of peritoneal irritation (40%) and one patient had abdominal distention (20%). All patients were submitted to laparotomies. In 20% there were no complications. In 80% was performed appendectomy complicated by suppuration (40%) or perforation (40%). Superficial infection of the surgical site occurred in two patients, requiring clinical management. The hospital stay ranged from 48 h to 45 days. Conclusion : Acute appendicitis after liver transplantation is a rare event being associated with a high rate of drilling, due to delays in diagnosis and therapy, and an increase in hospital stay. PMID:27120736

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

    Zhao-chun Chi; Quan-jiang Dong; Chang-xin Geng

    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.

  2. A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF-5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases

    Nalpas, Bertrand; Ichaï, Philippe; Jamot, Laure; Carbonell, Nicolas; Rudler, Marika; Mathurin, Philippe; Durand, François; Gerken, Guido; Manns, Michael; Trautwein, Christian; Larrey, Dominique; Radenne, Sylvie; Duvoux, Christophe; Leroy, Vincent; Bernuau, Jacques; Faivre, Jamila; Moniaux, Nicolas; Bréchot, Christian; Amouyal, Gilles; Amouyal, Paul; Samuel, Didier

    2016-01-01

    Objective No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. Design double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately. Results 57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02). Conclusion ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH. Trial Registration ClinicalTrials.gov NCT01318525 PMID:26983031

  3. A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF-5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases.

    Bertrand Nalpas

    Full Text Available No efficient medical treatment is available for severe acute hepatitis (SAH except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH.double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72. Intention to treat (ITT and per-protocol (PP analysis of the entire group and the Hepatitis B virus (HBV/AIH (auto-immune hepatitis sub-group were done separately.57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10, HBV (n = 13, AIH (n = 9, drug-induced (n = 8, other (n = 17. On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32, nor the transplant-free survival rate at day 21 (75 vs 86% differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04; the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02.ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH.ClinicalTrials.gov NCT01318525.

  4. Acute liver injury induced by weight-loss herbal supplements

    Gary C Chen, Vivek S Ramanathan, David Law, Pauline Funchain, George C Chen, Samuel French, Boris Shlopov, Viktor Eysselein, David Chung, Sonya Reicher, Binh V Pham

    2010-01-01

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a caut...

  5. Acute renal dysfunction in liver diseases

    2007-01-01

    Renal dysfunction is common in liver diseases, either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. The presence of renal impairment in both groups is a poor prognostic indicator. Renal failure is often multifactorial and can present as pre-renal or intrinsic renal dysfunction. Obstructive or post renal dysfunction only rarely complicates liver disease. Hepatorenal syndrome (MRS) is a unique form of renal failure associated with advanced liver disease or cirrhosis, and is characterized by functional renal impairment without significant changes in renal histology. Irrespective of the type of renal failure, renal hypoperfusion is the central pathogenetic mechanism, due either to reduced perfusion pressure or increased renal vascular resistance. Volume expansion, avoidance of precipitating factors and treatment of underlying liver disease constitute the mainstay of therapy to prevent and reverse renal impairment. Splanchnic vasoconstrictor agents, such as terlipressin, along with volume expansion, and early placement of transjugular intrahepatic portosystemic shunt (TIPS) may be effective in improving renal function in HRS. Continuous renal replacement therapy (CRRT) and molecular absorbent recirculating system (MARS) in selected patients may be life saving while awaiting liver transplantation.

  6. Prognostic models for acute liver failure

    Wei-Bo Du; Xiao-Ping Pan; Lan-Juan Li

    2010-01-01

    BACKGROUND: Acute liver failure (ALF) remains a dramatic and unpredictable disease with high morbidity and mortality. Early and accurate prognostic assessment of patients with ALF is critically important for optimum clinical pathway. DATA SOURCES: Five English-language medical databases, MEDLINE, ScienceDirect, OVID, Springer Link and Wiley Interscience were searched for articles on"acute liver failure","prognosis", and related topics. RESULTS: Multi-variable prognostic models including the King's College Hospital criteria and the model for end-stage liver disease score have been widely used in determination of the prognosis of ALF, but the results are far from satisfactory. Other prognostic indicators including serum Gc-globulin, arterial blood lactate, serum phosphate, arterial blood ammonia, and serum alpha-fetoprotein are promising but await further assessement. CONCLUSIONS: A reliable prognostic model to be developed in the future should not only have predictive value for poor outcome but also help to predict the survival of patients without a liver transplantation. Further studies are necessary to assess the prognostic accuracy of any new models.

  7. Acetaminophen induces a caspase-dependent and Bcl-XL sensitive apoptosis in human hepatoma cells and lymphocytes.

    Boulares, A Hamid; Zoltoski, Anna J; Stoica, Bogdan A; Cuvillier, Olivier; Smulson, Mark E

    2002-01-01

    Acetaminophen is a widely used analgesic and antipyretic drug that exhibits toxicity at high doses to the liver and kidneys. This toxicity has been attributed to cytochrome P-450-generated metabolites which covalently modify target proteins. Recently, acetaminophen, in its unmetabolized form, has been shown to affect a variety of cells and tissues, for instance, testicular and lymphoid tissues and lymphocyte cell lines. The effects on cell viability of acetaminophen at a concentration comparable to that achieved in plasma during acetaminophen toxicity have now been examined with a hepatoma cell line SK-Hep1, primary human peripheral blood lymphocytes and human Jurkat T cells. Acetaminophen reduced cell viability in a time-dependent manner. Staining of cells with annexin-V also revealed that acetaminophen induced, after 8 hr of treatment, a loss of the asymmetry of membrane phospholipids, which is an early event associated with apoptosis. Acetaminophen triggered the release of cytochrome c from mitochondria into the cytosol, activation of caspase-3, 8, and 9, cleavage of poly(ADP-ribose) polymerase, and degradation of lamin B1 and DNA. Whereas cleavage of DNA into internucleosomal fragments was apparent in acetaminophen treated SK-Hep1 and primary lymphocytes, DNA was only degraded to 50-kb fragments in treated Jurkat cells. Overexpression of the antiapoptotic protein Bcl-XL prevented these various apoptotic events induced by acetaminophen in Jurkat cells. Caspase-8 activation was a postmictochondrial event and occurred in a Fas-independent manner. These results demonstrate that acetaminophen induces caspases-dependent apoptosis with mitochondria as a primary target. These results also reiterate the potential role of apoptosis in acetaminophen hepatic and extrahepatic toxicity. PMID:12005112

  8. Imatinib-induced fatal acute liver failure

    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.

  9. Acute Renal Failure in Liver Transplant Patients: Indian Study

    Naik, Pradeep; Premsagar, B.; Mallikarjuna, M.

    2013-01-01

    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 tac...

  10. Dengue fever with acute liver failure

    Vinodh B; Bammigatti C; Kumar Ashok; Mittal V

    2005-01-01

    A virus belonging to the Flaviviridae group causes dengue haemorrhagic fever. Dengue presenting as acute liver failure is rare. Dengue is endemic in India. The last epidemic of dengue occurred in Delhi in 2003. During this epidemic, 2185 confirmed cases of dengue were reported. Dengue virus serotypes 2 and 3 were responsible for this epidemic. A 19-yr-old male presented to our hospital with the complaints of fever for 12 days, during this epidemic. He was diagnosed as having dengue shock synd...

  11. MODULATION OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY BY THE XENOBIOTIC RECEPTOR CAR

    We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR-...

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

    Aron, Jonathan; Agarwal, Banwari; Davenport, Andrew

    2016-04-01

    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. PMID:26894968

  13. Acute liver injury induced by weight-loss herbal supplements.

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss. PMID:21173910

  14. Acute liver failure associated with Garcinia cambogia use.

    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. PMID:26626648

  15. LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

    Nacif, Lucas Souto; Pinheiro, Rafael Soares; PÉCORA, Rafael Antônio de Arruda; Ducatti, Liliana; ROCHA-SANTOS, Vinicius; Andraus, Wellington; D'ALBUQUERQUE, Luiz Carneiro

    2015-01-01

    Introduction: Late acute rejection leads to worse patient and graft survival after liver transplantation. Aim: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. Method: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were a...

  16. Steroid use in Acute Liver Failure

    Karkhanis, Jamuna; Verna, Elizabeth C.; Chang, Matthew S.; Stravitz, R. Todd; Schilsky, Michael; Lee, William M; Brown, Robert S

    2014-01-01

    Background/Aims 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. Methods 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). Results 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% vs. 66%, p=0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of MELD (MELD > 40, survival 30% vs. 57%, p=0.03). In multivariable analysis controlling for steroid use and diagnosis, age (OR 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07) and pHsteroid use was associated with a marginal benefit in SS overall (35% v. 23%, p=0.047), this benefit did not persistent in multivariable analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and ALT (1.02) were the only significant predictors of SS. Conclusions Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. PMID:23929808

  17. A case of acute viral hepatitis interfering with acute fatty liver disease of pregnancy

    Abdulkadir Turgut

    2013-03-01

    Full Text Available Acute hepatitis A is a rarely seen infection during pregnancy.In terms of clinical and laboratory findings, it can beinterfere with acute fatty liver disease which can be quitemortal during pregnancy. Since liver function tests are elevatedin both conditions, hepatitis A infection should alsobe kept in mind in differential diagnosis. We present a 30year-old pregnant woman with 35 weeks of gestation whopresented to our clinic with a suspection of acute fattyliver disease but finally diagnosed as acute hepatitis A infection.J Clin Exp Invest 2013; 4 (1: 123-125Key words: Hepatitis A, pregnancy, acute fatty liver disease

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

    Paul, Sudip; Islam, Md Aminul; Tanvir, E M; Ahmed, Romana; Das, Sagarika; Rumpa, Nur-E-Noushin; Hossen, Md Sakib; Parvez, Mashud; Gan, Siew Hua; Khalil, Md Ibrahim

    2016-01-01

    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. PMID:27034701

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

    Paul, Sudip; Islam, Md. Aminul; Tanvir, E. M.; Ahmed, Romana; Das, Sagarika; Rumpa, Nur-E-Noushin; Hossen, Md. Sakib; Parvez, Mashud; Gan, Siew Hua; Khalil, Md. Ibrahim

    2016-01-01

    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. PMID:27034701

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

    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.

  1. Liver cold preservation induce lung surfactant changes and acute lung injury in rat liver transplantation

    An Jiang; Chang Liu; Feng Liu; Yu-Long Song; Quan-Yuan Li; Liang Yu; Yi Lv

    2012-01-01

    AIM: To investigate the relationship between donor liver cold preservation, lung surfactant (LS) changes and acute lung injury (ALI) after liver transplantation. METHODS: Liver transplantation models were established using male Wistar rats. Donor livers were preserved in University of Wisconsin solution at 4  °C for different lengths of time. The effect of ammonium pyrrolidinedithiocarbamate (PDTC) on ALI was also detected. All samples were harvested after 3 h reperfusion. ...

  2. Redox Nanoparticle Therapeutics for Acetaminophen-Induced Hepatotoxicity in Mice

    Boonruamkaew, Phetcharat; Chonpathompikunlert, Pennapa; Nagasaki, Yukio

    2016-01-01

    The purpose of this study was to evaluate the hepatoprotective effect of an antioxidative nanoparticle (RNPN) recently developed against APAP-induced hepatotoxicity in mice. The effects of oral administration of RNPN to APAP-treated mice were assessed for various biochemical liver function parameters: alanine transaminase (ALT) activity, aspartate transaminase (AST) activity, alkaline phosphatase (ALP) activity, prothrombin time, and serum albumin (ALB) level. The treatment effects were asses...

  3. [Acute cholangitis secondary to ascariasis and complicated by liver abscesses].

    Rakotonaivo, A; Ranoharison, H D; Razarimahefa, S H; Rakotozafindrabe, R; Rabenjanahary, T H; Ramanampamonjy, R M

    2015-01-01

    Acute cholangitis secondary to ascariasis is rare and occurs mainly in areas of high endemicity. The clinical presentation is non-specific, sometimes complicated by liver abscess. Abdominal ultrasound plays an important role in diagnosis and therapeutic surveillance. We report the case of a 35-year-old Malagasy woman with an acute cholangitis secondary to ascariasis and complicated by liver abscesses and its course to full recovery under medical treatment. PMID:26742557

  4. Torsion of Pedunculated Accessory Liver Lobe with Acute Acalculous Cholecystitis

    Khandelwal, Kamlesh K.; Gomes, Rachel M.; Bhagvat, Vikrant

    2012-01-01

    Accessory lobes of the liver are very uncommon and rarely symptomatic. We report the occurrence of torsion and infarction of a pedunculated accessory lobe of the liver with acute cholecystitis. The speculated possibilities of the coexistent pathologies and its management are discussed.

  5. Heparin-induced thrombocytopenia associated with acute liver graft failure

    Pannicke, Nadine; Pollok, Joerg-Matthias; Kluge, Stefan; Petzoldt, Martin

    2012-01-01

    An orthotopic liver transplantation (OLT) is of a proven benefit in an acute liver failure (ALF). Heparin-induced thrombocytopenia (HIT) is strongly associated with thromboembolic complications. We present the case of a 56-year-old patient who underwent an OLT owing to an ALF of unknown aetiology. HIT type II with consecutive hepatic and portal vein thrombosis caused progressive graft failure. Total hepatectomy and porto-caval shunt were performed to reduce the toxic effects of liver cell nec...

  6. Redox Nanoparticle Therapeutics for Acetaminophen-Induced Hepatotoxicity in Mice

    Boonruamkaew, Phetcharat; Chonpathompikunlert, Pennapa; Nagasaki, Yukio

    2016-01-01

    The purpose of this study was to evaluate the hepatoprotective effect of an antioxidative nanoparticle (RNPN) recently developed against APAP-induced hepatotoxicity in mice. The effects of oral administration of RNPN to APAP-treated mice were assessed for various biochemical liver function parameters: alanine transaminase (ALT) activity, aspartate transaminase (AST) activity, alkaline phosphatase (ALP) activity, prothrombin time, and serum albumin (ALB) level. The treatment effects were assessed in terms of free radical parameters: malondialdehyde (MDA) accumulation, glutathione peroxidase (GPx) activity, % inhibition of superoxide anion (O2−∙), and histopathological examination. The N-acetylcysteine (NAC)-treated group exhibited an enhanced prothrombin time relative to the control group, while RNPN did not prolong prothrombin time. The RNPN-treated animals exhibited lower levels of ALT, AST, and ALP, while increased ALB levels were measured in these animals compared to those in the other groups. The RNPN-treated animals furthermore exhibited improved MDA levels, GPx activity, and % inhibition of O2−∙, which relate to oxidative damage. Histological staining of liver tissues from RNPN-treated animals did not reveal any microscopic changes relative to the other groups. The findings of this study suggest that RNPN possesses effective hepatoprotective properties and does not exhibit the notable adverse effects associated with NAC treatment. PMID:27073589

  7. A case of acute viral hepatitis interfering with acute fatty liver disease of pregnancy

    Abdulkadir Turgut; Ali Özler; Neval Yaman Görük; Senem Yaman Tunç; Nurullah Peker; Recep Tekin

    2013-01-01

    Acute hepatitis A is a rarely seen infection during pregnancy.In terms of clinical and laboratory findings, it can beinterfere with acute fatty liver disease which can be quitemortal during pregnancy. Since liver function tests are elevatedin both conditions, hepatitis A infection should alsobe kept in mind in differential diagnosis. We present a 30year-old pregnant woman with 35 weeks of gestation whopresented to our clinic with a suspection of acute fattyliver disease but finally diagnosed ...

  8. Montelukast induced acute hepatocellular liver injury

    Harugeri A

    2009-01-01

    Full Text Available A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM and Naranjo′s algorithm was ′probable′. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.

  9. Donor liver natural killer cells alleviate liver allograft acute rejection in rats

    Jian-Dong Yu; Tian-Zhu Long; Guo-Lin Li; Li-Hong Lv; Hao-Ming Lin; Yong-Heng Huang; Ya-Jin Chen; Yun-Le Wan

    2011-01-01

    BACKGROUND: Liver enriched natural killer (NK) cells are of high immune activity. However, the function of donor liver NK cells in allogeneic liver transplantation (LTx) remains unclear. METHODS: Ten Gy of whole body gamma-irradiation (WBI) from a 60Co source at 0.6 Gy/min was used for depleting donor-derived leukocytes, and transfusion of purified liver NK cells isolated from the same type rat as donor (donor type liver NK cells, dtlNKs) through portal vein was performed immediately after grafting the irradiated liver. Post-transplant survival observation on recipients and histopathological detection of liver grafts were adoptive to evaluate the biological impact of donor liver NK cells on recipients' survival in rat LTx. RESULTS: Transfusion of dtlNKs did not shorten the survival time among the recipients of spontaneous tolerance model (BN to LEW rat) after rat LTx, but prolonged the liver graft survival among the recipients depleted of donor-derived leukocytes in the acute rejection model (LEW to BN rat). Compared to the recipients in the groups which received the graft depleted of donor-derived leukocytes, better survival and less damage in the allografts were also found among the recipients in the two different strain combinations of liver allograft due to transfusion of dtlNKs. CONCLUSIONS: Donor liver NK cells alone do not exacerbate liver allograft acute rejection. Conversely, they can alleviate it, and improve the recipients' survival.

  10. Current status of auxiliary partial orthotopic liver transplantation for acute liver failure.

    Rela, Mohamed; Kaliamoorthy, Ilankumaran; Reddy, Mettu Srinivas

    2016-09-01

    Auxiliary partial orthotopic liver transplantation (APOLT) is a technique of liver transplantation (LT) where a partial liver graft is implanted in an orthotopic position after leaving behind a part of the native liver. APOLT was previously considered technically challenging with results inferior to orthotopic liver transplantation. Results of this procedure have continued to improve with improving surgical techniques and a better understanding of the natural history of acute liver failure (ALF) and liver regeneration. The procedure is being increasingly accepted as a valid treatment option for ALF-especially in children. This article reviews the historical background to this operation, advances in the technique, and its current place in the management of ALF. Liver Transplantation 22 1265-1274 2016 AASLD. PMID:27357489

  11. Gastric emptying in rats with acetaminophen-induced hepatitis

    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.

  12. Spathodea campanulata Extract Attenuates Acetaminophen-Induced Hepatic Injury in Mice

    Phyllis Elsie Dadzeasah; Charles Ansah

    2013-01-01

    Spathodea campanulata, well known for its traditional medicinal uses was investigated for hepatoprotective activity against acetaminophen-induced hepatic damage in mice. Six groups of mice were pre-treated with 100, 300 and 625 mg/kg of the aqueous extract of Spathodea campanulata stem bark, N-acetyl cysteine (300 mg/kg; p.o) or distilled water for 5 days before they were intoxicated with a single dose of acetaminophen (600 mg/kg; p.o). Alanine aminotransferase, Aspartate aminotransferase an...

  13. Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice

    Peng, Yuan; Chen, Qian; Yang, Tao; Tao, Yanyan; Lu, Xiong; Liu, Chenghai

    2014-01-01

    Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and d-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phe...

  14. Acute-on-chronic liver failure due to bacterial infection in liver cirrhosis: causes and management

    Han, Tao

    2015-01-01

    Bacterial infection is a common complication in patients with liver cirrhosis, and acute-on-chronic liver failure due to bacterial infection has become a serious clinical problem. There are still many problems in the research on the pathogenesis and management of bacterial infection in liver cirrhosis, such as insidious onset, difficult early diagnosis, and increased multi-drug resistant bacteria. This article reviews the research progress in the causes and management of bacterial infection i...

  15. Sonographic changes of liver and gallbladder in acute viral hepatitis

    Ebrahimi Daryani N

    2001-07-01

    Full Text Available Hepatomegaly, decrease in the liver paranchymal echo and increase in the gallbladder wall thickness has been shown in acute viral hepatitis. The present study was done to determine sonographic changes in acute viral hepatitis. We performed liver and bile ducts sonography and specific tests on 42 patients (mean age: 31.5 and 61% male with acute viral hepatitis. Gallbladder wall thickness was seen in 45.2% and hepatomegaly in 33.3% of patients and liver paranchymal echo was decreased in 19.3%. Age, sex, type of hepatitis, cholecystitis like symptoms, aspartate aminotransfrase, alanine aminotransfrase, alkaline phosphatase and bilirubin did not significantly corralate with these changes. Only raised prothrombin time was strongly correlated to the thickening of the gallbladder and decrease in the liver paranchymal echo and cholesistic like symptoms we can postulate that thickening of the gallbladder and decrease in the liver paranchymal echo is not dependent on the severity and speed of the paranchymal necrosis (as considered with ALT and AST but they depend on the liver function disturbance (as considered with PT because the thickening of the gall bladder is present in 45% of the patients and 10% of the normal population have gallbladder stones, one should not perform the diagnosis of acute cholecystitis, only on the basis of sonographic report without attention to the clinical and laboratory data.

  16. Montelukast induced acute hepatocellular liver injury

    Harugeri A; Parthasarathi G; Sharma J; D′Souza G; Ramesh M

    2009-01-01

    A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast i...

  17. Acute Liver Toxicity due to Efavirenz/Emtricitabine/Tenofovir

    Rashmee Patil

    2015-01-01

    Full Text Available The fixed-dose combination of Efavirenz/Emtricitabine/Tenofovir is a first-line agent for the treatment of HIV; however few cases have reported hepatotoxicity associated with the drug. We report a case of Efavirenz/Emtricitabine/Tenofovir-associated hepatotoxicity presenting mainly with hepatocellular injury characterized by extremely elevated aminotransferase levels, which resolved without acute liver failure or need for liver transplant referral.

  18. Hepatitis E and Acute Liver Failure in Pregnancy

    Shalimar; Acharya, Subrat K.

    2013-01-01

    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 c...

  19. Liver dialysis in acute-on-chronic liver failure: current and future perspectives.

    Maiwall, Rakhi; Maras, Jaswinder Singh; Nayak, Suman Lata; Sarin, Shiv Kumar

    2014-09-01

    Patients with acute-on-chronic liver failure (ACLF) are known to have a very high mortality rate as the majority of these patients succumb to multiorgan failure. Liver transplant remains the only option for these patients; however, there are problems with its availability, cost and also the complications and side effects associated with immunosuppression. Unlike advanced decompensated liver disease, there is a potential for hepatic regeneration and recovery in patients with ACLF. A liver support system, cell or non-cell based, logically is likely to provide temporary functional support until the donor liver becomes available or the failing liver survives the onslaught of the acute insult and spontaneously regenerates. Understanding the pathogenesis of liver failure and regeneration is essential to define the needs for a support system. Removal of hepatotoxic metabolites and inhibitors of hepatic regeneration by liver dialysis, a non-cell-based hepatic support, could help to provide a suitable microenvironment and support the failing liver. The current systems, i.e., MARS and Prometheus, have failed to show survival benefits in patients with ACLF based on which newer devices with improved functionality are currently under development. However, larger randomized trials are needed to prove whether these devices can enable restoration of the complex dysregulated immune system and impact organ failure and mortality in these patients. PMID:26201332

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

    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....

  1. Recurrent Acute Liver Failure Because of Acute Hepatitis Induced by Organic Solvents

    Ito, Daisuke; Tanaka, Tomohiro; Akamatsu, Nobuhisa; Ito, Kyoji; Hasegawa, Kiyoshi; Sakamoto, Yoshihiro; Nakagawa, Hayato; Fujinaga, Hidetaka; Kokudo, Norihiro

    2016-01-01

    Abstract The authors present a case of recurrent acute liver failure because of occupational exposure to organic solvents. A 35-year-old man with a 3-week history of worsening jaundice and flu-like symptoms was admitted to our hospital. Viral hepatitis serology and autoimmune factors were negative. The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. Four months after discharge, the patient's liver function worsened again. The authors considered the possibility of antinuclear antibody-negative autoimmune hepatitis and initiated steroid treatment, which was effective. Four months after discharge, the patient was admitted for repeated liver injury. The authors started him on steroid pulse therapy, but this time it was not effective. Just before the first admission, he had started his own construction company where he was highly exposed to organic solvents, and thus the authors considered organic solvent-induced hepatitis. Although urine test results for organic solvents were negative, a second liver biopsy revealed severe infiltration of neutrophils, compatible with toxic hepatitis. Again, his liver function spontaneously improved. Based on the pathology and detailed clinical course, including the patient's high exposure to organic solvents since just before the first admission, and the spontaneous recovery of his liver damage in the absence of the exposure, he was diagnosed with toxic hepatitis. The authors strongly advised him to avoid organic solvents. Since then, he has been in good health without recurrence. This is the first report of recurrent acute liver failure because of exposure to organic solvents, which was eventually diagnosed through a meticulous medical history and successfully recovered by avoiding the causative agents. In acute liver failure with an undetermined etiology, clinicians

  2. Recurrent Acute Liver Failure Because of Acute Hepatitis Induced by Organic Solvents: A Case Report.

    Ito, Daisuke; Tanaka, Tomohiro; Akamatsu, Nobuhisa; Ito, Kyoji; Hasegawa, Kiyoshi; Sakamoto, Yoshihiro; Nakagawa, Hayato; Fujinaga, Hidetaka; Kokudo, Norihiro

    2016-01-01

    The authors present a case of recurrent acute liver failure because of occupational exposure to organic solvents. A 35-year-old man with a 3-week history of worsening jaundice and flu-like symptoms was admitted to our hospital. Viral hepatitis serology and autoimmune factors were negative. The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. Four months after discharge, the patient's liver function worsened again. The authors considered the possibility of antinuclear antibody-negative autoimmune hepatitis and initiated steroid treatment, which was effective. Four months after discharge, the patient was admitted for repeated liver injury. The authors started him on steroid pulse therapy, but this time it was not effective. Just before the first admission, he had started his own construction company where he was highly exposed to organic solvents, and thus the authors considered organic solvent-induced hepatitis. Although urine test results for organic solvents were negative, a second liver biopsy revealed severe infiltration of neutrophils, compatible with toxic hepatitis. Again, his liver function spontaneously improved. Based on the pathology and detailed clinical course, including the patient's high exposure to organic solvents since just before the first admission, and the spontaneous recovery of his liver damage in the absence of the exposure, he was diagnosed with toxic hepatitis. The authors strongly advised him to avoid organic solvents. Since then, he has been in good health without recurrence. This is the first report of recurrent acute liver failure because of exposure to organic solvents, which was eventually diagnosed through a meticulous medical history and successfully recovered by avoiding the causative agents. In acute liver failure with an undetermined etiology, clinicians should rule

  3. [Acute liver failure after ingestion of death cap mushrooms].

    Zuliani, Anna-Maria; Kabar, Iyad; Mitchell, Todd; Heinzow, Hauke Sebastian

    2016-07-01

    Amatoxins, which are mainly found in Amanita phalloides, Amanita virosa, and Galerina autumnalis, are responsible for the majority of fatal intoxication with green death cap. The intoxication is associated with acute liver failure, which explains the poor prognosis. Acute liver injury is generally preceeded by a gastrointestinal phase with nausea, vomiting and diarrhea. In the course, pre-renal kidney failure due to the associated fluid deficit and fulminant liver failure may occur. General guidelines for the treatment of amatoxin poisoning are yet not available. We report on three patients who suffered from amatoxin mushroom poisoning after ingestion of green death cap mushrooms. Based on the pathophysiology of amatoxin poisoning, we discuss a potential therapeutic approach. PMID:27359312

  4. Oroxylin A accelerates liver regeneration in CCl₄-induced acute liver injury mice.

    Runzhi Zhu

    Full Text Available INTRODUCTION: Based on the previous research that oroxylin A can suppress inflammation, we investigated the hepatoprotective role of oroxylin A against CCl₄-induced liver damage in mice and then studied the possible alteration of the activities of cytokine signaling participating in liver regeneration. Wild type (WT mice were orally administrated with oroxylin A (60 mg/kg for 4 days after CCl₄ injection, the anti-inflammatory effects of oroxylin A were assessed directly by hepatic histology and indirectly by measuring serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and Albumin. Proliferating cell nuclear antigen (PCNA staining was performed to evaluate the role of oroxylin A in promoting hepatocyte proliferation. Serum IL-1β, TNF-α, IL-6 and IL-1Ra levels were measured by enzyme-linked immunosorbent assay (ELISA and liver HGF, EGF, TNF-α, IL-6, IL-1Ra and IL-1β gene expression was determined by quantitative real-time PCR. The data indicated that the IL-6 and TNF-α mRNA of oroxylin A administered group significantly increased higher than the control within 12 hours after CCl4 treatment. Meanwhile, oroxylin A significantly enhanced the expression of IL-1Ra at the early phase, which indicated that oroxylin A could facilitate the initiating events in liver regeneration by increasing IL-1Ra which acts as an Acute-Phase Protein (APP. In addition, a lethal CCl₄-induced acute liver failure model offers a survival benefit in oroxylin A treated WT mice. However, oroxylin A could not significantly improve the percent survival of IL-1RI⁻/⁻ mice with a lethal CCl₄-induced acute liver failure. CONCLUSIONS: Our study confirmed that oroxylin A could strongly promote liver structural remodeling and functional recovery through IL-1Ra/IL-1RI signaling pathway. All these results support the possibility of oroxylin A being a therapeutic candidate for acute liver injury.

  5. Outcome of acute liver failure in the elderly

    Schiødt, Frank V; Chung, Raymond T; Schilsky, Michael L;

    2009-01-01

    Older age is considered a poor prognostic factor in acute liver failure (ALF) and may still be considered a relative contraindication for liver transplantation for ALF. We aimed to evaluate the impact of older age, defined as age > or = 60 years, on outcomes in patients with ALF. One thousand one...... 48.2% in group 2 for non-acetaminophen patients (P < 0.001). The spontaneous survival rate (ie, survival without liver transplantation) was 64.9% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 30.8% in group 1 and 24.7% in group 2 for non-acetaminophen patients (P...... = 0.27). Age was not a significant predictor of spontaneous survival in multiple logistic regression analyses. Group 2 patients were listed for liver transplantation significantly less than group 1 patients. Age was listed as a contraindication for transplantation in 5 patients. In conclusion, in...

  6. Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation.

    Crespo, Gonzalo; Castro-Narro, Graciela; García-Juárez, Ignacio; Benítez, Carlos; Ruiz, Pablo; Sastre, Lydia; Colmenero, Jordi; Miquel, Rosa; Sánchez-Fueyo, Alberto; Forns, Xavier; Navasa, Miquel

    2016-03-01

    Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post-liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy-proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)-infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment. Liver Transpl 22:298-304, 2016. © 2015 AASLD. PMID:26609794

  7. Effect of corn silk extract on acetaminophen induced renal damage in mice

    To evaluate the protective role of Corn Silk extract on Acetaminophen induced nephrotoxicity in albino mice. Study Design: Laboratory based randomized controlled trials. Place and Duration of Study: The study was carried out in experimental research laboratory University of Health Sciences and Anatomy department, Lahore. The study duration was one year from February 2012 to February 2013. Material and Methods: Twenty seven male albino mice, 6-8 weeks old weighing 30 + 5 gm, were used; these animals were randomly divided into three groups having nine mice in each group. Group A served as control and was given 16.6ml/kg normal saline intraperitoneally on first day of experiment and was sacrificed on 10th day of the experiment. Group B was treated with acetaminophen 600 mg/kg dissolved in 16.6 ml of normal saline intraperitoneally on 1st day of experiment and was sacrificed after 48 hours. Group C was given acetaminophen at a dose of 600 mg/kg intraperitoneally on first day of experiment and then corn silk extract was given by oral route at a dose of 400 mg/kg for next 8 days. The animals were sacrificed on 10th day of the experiment, the kidneys were removed; 3mm three tissue pieces were fixed in 10% formaline; processed and stained with H and E for histological study. Results: It was observed on microscopic examination that Corn silk extract reduced deleterious effects of acetaminophen on tubules of kidney as evidenced by reduction of tubular vacuolation and necrosis, absence of protein casts, vascular congestion and inflammation. Conclusion: It is concluded from current results that corn silk extract protects acetaminophen induced nephrotoxicity. (author)

  8. Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury.

    Li, San-Qiang; Zhu, Sha; Wan, Xue-Dong; Xu, Zheng-Shun; Ma, Zhao

    2014-04-01

    Although some studies have described the function of ADAM8 (a disintegrin and metalloprotease 8) related with rheumatoid arthritis, cancer and asthma, etc., the concrete role of ADAM8 in acute liver injury is still unknown. So mice respectively received anti-ADAM8 monoclonal antibody (mAb) of 100 μg/100 μl, 200 μg/100 μl or 300 μg/100 μl in PBS or PBS pre-injection. Then acute liver injury was induced in the mice by intraperitoneal (i.p.) injection of carbon tetrachloride (CCl₄). Serum AST and ALT level, Haematoxylin-eosin (H&E) staining, the expression level of vascular endothelial growth factor (VEGF), cytochrome P450 1A2 (CYP1A2) and proliferating cell nuclear antigen (PCNA) were detected in the mice after CCl4 administration. Our results showed that anti-ADAM8 mAb pre-injection could effectively lower AST and ALT levels (P < 0.05 or P < 0.01) and reduce liver injury (P < 0.05 or P <0.01), induce the expression of VEGF, CYP1A2 and PCNA (P <0.05 or P < 0.01) in dose-dependent manner compared with the control mice which received PBS pre-injection. In summary, our study suggested that ADAM8 might promote liver injury by inhibiting the proliferation of hepatocytes, angiogenesis and affecting the metabolism function of liver during acute liver injury induced by CCl₄. Anti-ADAM8 mAb injection might be suitable as a potential method for acute liver injury therapy. PMID:24646716

  9. Liver transplantation for acute intermittent porphyria:a viable treatment?

    Faisal S Dar; Koji Asai; Ali Raza Haque; Thomas Cherian; Mohamed Rela; Nigel Heaton

    2010-01-01

    BACKGROUND:Acute intermittent porphyria (AIP) is the most common hepatic porphyria. Its clinical presentation includes severe disabling and life-threatening neurovisceral symptoms and acute psychiatric symptoms. These symptoms result from the overproduction and accumulation of porphyrin precursors, 5-aminoleuvulinic acid (ALA) and porphobilinogen (PBG). The effect of medical treatment is transient and is not effective once irreversible neurological damage has occurred. Liver transplantation (LT) replaces hepatic enzymes and can restore normal excretion of ALA and PBG and prevent acute attacks. METHOD:Two cases of LT for AIP were identiifed retro-spectively from a prospectively maintained LT database. RESULT:LT was successful with resolution of AIP in two patients who suffered from repeated acute attacks. CONCLUSION:LT can correct the underlying metabolic abnormality in AIP and improves quality of life signiifcantly.

  10. Steroid use in acute liver failure

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

    2014-01-01

    , survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61......% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.......03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH steroid use was associated with a marginal benefit...

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

    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.

  12. Percutaneous liver biopsy complicated by hemobilia-associated acute cholecystitis

    Yair Edden; Hugo St Hilaire; Keith Benkov; Michael T Harris

    2006-01-01

    Liver biopsy is generally considered a safe and highly useful procedure. It is frequently performed in an outpatient setting for diagnosis and follow-up in numerous liver disorders. Since its introduction at the end of the 19th century, broad experience, new imaging techniques and special needles have significantly reduced the rate of complications associated with liver biopsy. Known complications of percutaneous biopsy of the liver include hemoperitoneum, subcapsular hematoma, hypotension, pneumothorax and sepsis.Other intra-abdominal complications are less common.Hemobilia due to arterio-biliary duct fistula has been described, which has only rarely been clinically expressed as cholecystitis or pancreatitis. We report a case of a fifteen year-old boy who developed severe acute cholecystitis twelve days after a percutaneous liver biopsy performed in an outpatient setting. The etiology was clearly demonstrated to be hemobilia-associated,and the clinical course required the performance of a laparoscopic cholecystectomy. The post operative course was uneventful and the patient was discharged home. Percutaneous liver biopsy is a safe and commonly performed procedure. However, severe complications can occasionally occur. Both medical and surgical options should be evaluated while dealing with these rare incidents.

  13. Characteristics and Discrepancies in Acute-on-Chronic Liver Failure: Need for a Unified Definition

    Kim, Tae Yeob; Song, Do Seon; Kim, Hee Yeon; Sinn, Dong Hyun; Yoon, Eileen L.; Kim, Chang Wook; Jung, Young Kul; Suk, Ki Tae; Lee, Sang Soo; Lee, Chang Hyeong; Kim, Tae Hun; Kim, Jeong Han; Choe, Won Hyeok; Yim, Hyung Joon; Kim, Sung Eun

    2016-01-01

    Background & Aim 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. Methods We collected retrospective data for 1470 hospitalized patients with chronic liver disease (CLD) and acute deterioration between January 2013 and Decem...

  14. Acute-on-chronic liver failure: a review

    Zamora Nava LE

    2014-04-01

    Full Text Available Luis Eduardo Zamora Nava,1 Jonathan Aguirre Valadez,2 Norberto C Chávez-Tapia,3 Aldo Torre21Department of Endoscopy, 2Department of Gastroenterology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, 3Obesity and Digestive Diseases Unit, Medica Sur Clinic and Foundation, Mexico City, MexicoAbstract: There is no universally accepted definition of acute-on-chronic liver failure; however, it is recognized as an entity characterized by decompensation from an underlying chronic liver disease associated with organ failure that conveys high short-term mortality, with alcoholism and infection being the most frequent precipitating events. The pathophysiology involves inflammatory processes associated with a trigger factor in susceptible individuals (related to altered immunity in the cirrhotic population. This review addresses the different definitions developed by leading research groups, epidemiological and pathophysiological aspects, and the latest treatments for this entity.Keywords: acute-on-chronic liver failure, cirrhosis, organ failure, acute kidney injury, infection

  15. Protective Effect of Chlormethiazole, a Sedative, against Acetaminophen-Induced Liver Injury in Mice

    Lee, Han Chu; Jung, Sung Ae; Jung, Hye Kyung; Yi, Sun Young; Kim, Doe Young; Moon, Il Hwan; Park, Sung Su

    1999-01-01

    Objectives The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole, a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazol...

  16. Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice.

    Peng, Yuan; Chen, Qian; Yang, Tao; Tao, Yanyan; Lu, Xiong; Liu, Chenghai

    2014-03-01

    Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model

  17. Economic evaluation of the artificial liver support system MARS in patients with acute-on-chronic liver failure

    Hessel Franz P

    2006-01-01

    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 I...

  18. Septic liver - Clinical relevance of early inhomogeneous enhancement of the liver in patients with acute pyelonephritis

    Han, Ga Jin; Lee, Nam Kyung; Kim, Suk [Dept. of Radiology, Biomedical Research Inst., Pusan National Univ. Hospital, Pusan National Univ. School of Medicine, Busan (Korea, Republic of)], e-mail: kimsuk@medimail.co.kr; Kim, Tae Un [Dept. of Radiology, Pusan National Univ. Yangsan Hospital, Pusan National Univ. School of Medicine, Yangsan (Korea, Republic of); Song, Sang Heon [Dept. of Internal Medicine, Biomedical Research Inst., Pusan National Univ. Hospital, Pusan National Univ. School of Medicine, Busan (Korea, Republic of); Kim, Hyun Sung; Jo, Hong Jae [Dept. of Surgery, Biomedical Research Inst., Pusan National Univ. Hospital, Pusan National Univ. School of Medicine, Busan (Korea, Republic of)

    2013-10-15

    Background: CT scans of patients with febrile illness occasionally show hepatobiliary changes, although infection does not originate in the hepatobiliary system. These findings may cause radiologists and clinicians to misrecognize hepatobiliary diseases and initiate an inappropriate treatment. Thus, it is important to recognize hepatobiliary CT findings in cases of extrahepatobiliary infectious disease. Purpose: To evaluate extrarenal CT manifestations in patients with acute pyelonephritis and to determine the correlation between these extrarenal CT findings and septic liver based on laboratory parameters of sepsis. Material and Methods: This study included 157 retrospectively identified patients with confirmed acute pyelonephritis based on CT imaging and urine test, and who had also undergone multi-phase dynamic contrast-enhanced CT scan. Two radiologists reviewed CT findings including early inhomogeneous enhancement of the liver, periportal low density and gallbladder edema, which were correlated with laboratory data including liver function enzymes, albumin, C-reactive protein, white blood cell count, and results of a blood culture by using the Fisher's exact test and Mann-Whitney U test. Results: Forty-six patients (29.3%) showed early inhomogeneous enhancement of the liver, which was associated with increased C-reactive protein (P < 0.001), a positive blood culture (P < 0.005), and decreased albumin level (P < 0.002). The periportal low density and gallbladder wall edema were noted in 15 patients (9.6%) and six patients (3.8%), respectively. These two CT findings were significantly associated with only decreased albumin level (P < 0.001 and P < 0.040). Conclusion: Early inhomogeneous enhancement of the liver in patients with acute pyelonephritis was significantly associated with increased CRP level, a positive blood culture and decreased albumin level, reflecting sepsis and sepsis-associated liver dysfunction, requiring rapid and appropriate intensive

  19. Septic liver - Clinical relevance of early inhomogeneous enhancement of the liver in patients with acute pyelonephritis

    Background: CT scans of patients with febrile illness occasionally show hepatobiliary changes, although infection does not originate in the hepatobiliary system. These findings may cause radiologists and clinicians to misrecognize hepatobiliary diseases and initiate an inappropriate treatment. Thus, it is important to recognize hepatobiliary CT findings in cases of extrahepatobiliary infectious disease. Purpose: To evaluate extrarenal CT manifestations in patients with acute pyelonephritis and to determine the correlation between these extrarenal CT findings and septic liver based on laboratory parameters of sepsis. Material and Methods: This study included 157 retrospectively identified patients with confirmed acute pyelonephritis based on CT imaging and urine test, and who had also undergone multi-phase dynamic contrast-enhanced CT scan. Two radiologists reviewed CT findings including early inhomogeneous enhancement of the liver, periportal low density and gallbladder edema, which were correlated with laboratory data including liver function enzymes, albumin, C-reactive protein, white blood cell count, and results of a blood culture by using the Fisher's exact test and Mann-Whitney U test. Results: Forty-six patients (29.3%) showed early inhomogeneous enhancement of the liver, which was associated with increased C-reactive protein (P < 0.001), a positive blood culture (P < 0.005), and decreased albumin level (P < 0.002). The periportal low density and gallbladder wall edema were noted in 15 patients (9.6%) and six patients (3.8%), respectively. These two CT findings were significantly associated with only decreased albumin level (P < 0.001 and P < 0.040). Conclusion: Early inhomogeneous enhancement of the liver in patients with acute pyelonephritis was significantly associated with increased CRP level, a positive blood culture and decreased albumin level, reflecting sepsis and sepsis-associated liver dysfunction, requiring rapid and appropriate intensive

  20. Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury

    Wancket, Lyn M.; Meng, Xiaomei; Rogers, Lynette K.; Liu, Yusen

    2012-01-01

    c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1+/+ and Mkp-1−/− mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechan...

  1. Acute fatty liver of pregnancy associated with severe acute pancreatitis: A case report

    Cássio; Vieira; de; Oliveira; Alecsro; Moreira; Julio; P; Baima; Leticia; de; C; Franzoni; Talles; B; Lima; Fabio; da; S; Yamashiro; Kunie; Yabuki; Rabelo; Coelho; Ligia; Y; Sassaki; Carlos; Antonio; Caramori; Ferno; G; Romeiro; Giovanni; F; Silva

    2014-01-01

    Acute fatty liver of pregnancy is a rare disease that affects women in the third trimester of pregnancy. Although infrequent, the disease can cause maternal mortality. The diagnosis is not always clear until the pregnancy is terminated, and significant complications, such as acute pancreatitis, can occur. Pancreatic involvement typically only occurs in severe cases after the development of hepatic and renal impairment. To date, little knowledge is available regarding how the disease causes pancreatitis. Treatment involves supportive measures and pregnancy interruption. In this report, we describe a case of a previously healthy 26-year-old woman at a gestational age of 27 wk and 6 d who was admitted with severe abdominal pain and vomiting. This case illustrates the clinical and laboratory overlap between acute fatty liver of pregnancy and pancreatitis, highlighting the difficulties in differentiating each disease. Furthermore, the hypothesis for this overlapping is presented, and the therapeutic options are discussed.

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

    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.

  3. Current Evidence for Extracorporeal Liver Support Systems in Acute Liver Failure and Acute-on-Chronic Liver Failure.

    Karvellas, Constantine J; Subramanian, Ram M

    2016-07-01

    Artificial (nonbiological) extracorporeal liver support devices aim to remove albumin-bound and water-soluble toxins to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while hepatic recovery or liver transplant occurs. The following beneficial effects have been documented: improvement of jaundice, amelioration of hemodynamic instability, reduction of portal hypertension, and improvement of hepatic encephalopathy. The only randomized prospective multicenter controlled trial to show an improvement in transplant-free survival was for high-volume plasmapheresis. Biological (cell-based) extracorporeal liver support systems aim to support the failing liver through detoxification and synthetic function and warrant further study for safety and benefit. PMID:27339682

  4. Late-onset acute rejection after living donor liver transplantation

    Nobuhisa Akamatsu; Yasuhiko Sugawara; Sumihito Tamura; Junichi Keneko; Yuichi Matsui; Kiyoshi Hasegawa; Masatoshi Makuuchi

    2006-01-01

    AIM: To investigate the incidence and risk factors of late-onset acute rejection (LAR) and to clarify the effectiveness of our immunosuppressive regime consisting of life-long administration of tacrolimus and steroids.METHODS: Adult living donor liver transplantation recipients (n = 204) who survived more than 6 mo after living donor liver transplantation were enrolled.Immunosuppression was achieved using tacrolimus and methylprednisolone. When adverse effects of tacrolimus were detected, the patient was switched to cyclosporine. Six months after transplantation,tacrolimus or cyclosporine was carefully maintained at a therapeutic level. The methylprednisolone dosage was maintained at 0.05 mg/kg per day by oral administration.Acute rejections that occurred more than 6 mo after the operation were defined as late-onset. The median followup period was 34 mo.RESULTS: LAR was observed in 15 cases (7%) and no chronic rejection was observed. The incidence of hyperlipidemia, chronic renal failure, new-onset posttransplantation diabetes, and deep fungal infection were 13%, 2%, 24%, and 17%, respectively. Conversion from tacrolimus to cyclosporine was required in 38 patients (19%). Multivariate analysis revealed that a cyclosporinebased regimen was significantly associated with LAR.CONCLUSION: Both LAR and drug-induced adverse events happen at a low incidence, supporting the safety and efficacy of the present immunosuppression regimen for living donor liver transplantation.

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

    Jepsen, Peter; Schmidt, Lars E; Larsen, Fin Stolze; Vilstrup, Hendrik

    2010-01-01

    Abstract Background: The prognosis for transplant-free survivors of paracetamol-induced acute liver failure is unknown. Aim: To examine whether paracetamol-induced acute liver failure increases long-term mortality. Methods: We followed all transplant-free survivors of paracetamol-induced acute liver injury hospitalized in a Danish national referral center during 1984-2004. We compared age-specific mortality rates from one year post-discharge through 2008 between those in wh...

  6. Protective mechanisms of garlic and wolfberry derivatives on acute and chronic liver injury animal models

    Xiao, Jia; 肖佳

    2012-01-01

    Liver is one of the most important organs in the body that maintains the homeostasis of metabolism, immunity, detoxification and hematopoiesis. A large number of acute and chronic intoxications and diseases can influence the normal functions of the liver, leading to irreversible liver damage and even cancer. Currently, applying herbs or herbal derivatives in the prevention and therapy of acute and chronic liver injury receive numerous attentions since they hold great potentials as food supple...

  7. Protective Effect of Sundarban Honey against Acetaminophen-Induced Acute Hepatonephrotoxicity in Rats

    Afroz, Rizwana; E. M. Tanvir; Hossain, Md. Fuad; Gan, Siew Hua; Parvez, Mashud; Aminul Islam, Md.; Khalil, Md Ibrahim

    2014-01-01

    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 hep...

  8. Attenuating Oxidative Stress by Paeonol Protected against Acetaminophen-Induced Hepatotoxicity in Mice

    Chen, Yuning; Deng, Yue; Zhi, Feng; Qian, Ke

    2016-01-01

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. The purpose of this study was to investigate whether paeonol protected against APAP-induced hepatotoxicity. Mice treated with paeonol (25, 50, 100 mg/kg) received 400 mg/kg acetaminophen intraperitoneally (i.p.) and hepatotoxicity was assessed. Pre-treatment with paeonol for 6 and 24 h ameliorated APAP-induced hepatic necrosis and significantly reduced the serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in a dose-dependent manner. Post-treatment with 100 mg/kg paeonol ameliorated APAP-induced hepatic necrosis and reduced AST and ALT levels in the serum after APAP administration for 24 h. Western blot revealed that paeonol inhibited APAP-induced phosphorylated JNK protein expression but not p38 and Erk1/2. Moreover, paeonol showed anti-oxidant activities with reducing hepatic MDA contents and increasing hepatic SOD, GSH-PX and GSH levels. Paeonol dose-dependently prevented against H2O2 or APAP-induced LDH releasing and ROS production in primary mouse hepatocytes. In addition, the mRNA levels of pro-inflammatory genes such as TNF-α, MCP-1, IL-1β and IL-6 in the liver were dose-dependently reduced by paeonol pre-treatment. Pre-treatment with paeonol significantly inhibited IKKα/β, IκBα and p65 phosphorylation which contributed to ameliorating APAP-induced hepatic inflammation. Collectively, the present study demonstrates paeonol has a protective ability against APAP-induced hepatotoxicity and might be an effective candidate compound against drug-induced acute liver failure. PMID:27144271

  9. Attenuating Oxidative Stress by Paeonol Protected against Acetaminophen-Induced Hepatotoxicity in Mice.

    Yi Ding

    Full Text Available Acetaminophen (APAP overdose is the most frequent cause of drug-induced acute liver failure. The purpose of this study was to investigate whether paeonol protected against APAP-induced hepatotoxicity. Mice treated with paeonol (25, 50, 100 mg/kg received 400 mg/kg acetaminophen intraperitoneally (i.p. and hepatotoxicity was assessed. Pre-treatment with paeonol for 6 and 24 h ameliorated APAP-induced hepatic necrosis and significantly reduced the serum alanine aminotransferase (ALT and aspartate transaminase (AST levels in a dose-dependent manner. Post-treatment with 100 mg/kg paeonol ameliorated APAP-induced hepatic necrosis and reduced AST and ALT levels in the serum after APAP administration for 24 h. Western blot revealed that paeonol inhibited APAP-induced phosphorylated JNK protein expression but not p38 and Erk1/2. Moreover, paeonol showed anti-oxidant activities with reducing hepatic MDA contents and increasing hepatic SOD, GSH-PX and GSH levels. Paeonol dose-dependently prevented against H2O2 or APAP-induced LDH releasing and ROS production in primary mouse hepatocytes. In addition, the mRNA levels of pro-inflammatory genes such as TNF-α, MCP-1, IL-1β and IL-6 in the liver were dose-dependently reduced by paeonol pre-treatment. Pre-treatment with paeonol significantly inhibited IKKα/β, IκBα and p65 phosphorylation which contributed to ameliorating APAP-induced hepatic inflammation. Collectively, the present study demonstrates paeonol has a protective ability against APAP-induced hepatotoxicity and might be an effective candidate compound against drug-induced acute liver failure.

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

    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

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

    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

  12. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.

    Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

    2016-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent. PMID:27161000

  13. Clinical and pathological analysis of acute rejection following orthotopic liver transplantation

    MA Yi; WANG Guo-dong; HE Xiao-shun; LI Jun-liang; ZHU Xiao-feng; HU Rui-de

    2009-01-01

    Background Acute rejection is one of the most important factors for prognosis following liver transplantation. With the use of potent immunosuppressants, acute rejection does not always present typical manifestations. Moreover, other complications often occur concomitantly after liver transplantation, which makes early diagnosis of acute rejection more difficult. Acute rejection is best diagnosed by liver biopsy. Differentiation of clinical manifestations and pathological features plays an important role in achieving individualized immunosuppressive treatment and prolonging long term survival of patients given orthotopic liver transplants.Methods From January 2004 to December 2006, 516 orthotopic liver transplantations were performed at the First Affiliated Hospital, Sun Yat-sen University. For patients who suffered acute rejection, clinical manifestations, histopathological features, diagnosis and anti-rejection treatment were summarized and analyzed. Results In 86 cases (16.7%), of the 516 recipients, 106 episodes of acute rejection occurred, which included 9 with histopathological borderline changes, 36 Banff Ⅰ rejections, 48 Banff Ⅱ and 13 Banff Ⅲ. Among these, 36 were cured by adjusting the dose of immunosuppressant and 65 were reversed by methylprednisolone pulse treatment. Five were methylprednisolone resistant, 3 of whom were given OKT3 treatment and 2 underwent liver retransplantation. Conclusions Due to potent immunosuppressive agents, acute rejection following an orthotopic liver transplantation lacks typical clinical manifestations and pathological features. Acute rejection is best diagnosed by liver biopsy. Designing rational individualized immunosuppressive regimen based on clinical and pathological features of acute rejection plays an important role in prolonging long term survival of patients.

  14. Expression of ECM proteins fibulin-1 and -2 in acute and chronic liver disease and in cultured rat liver cells

    Piscaglia, Fabio; Dudás, József; Knittel, Thomas; Rocco, Paola; Kobold, Dominik; Saile, Bernhard; Zocco, Maria; Timpl, Rupert; Ramadori, Giuliano

    2009-01-01

    Fibulin-2 has previously been considered as a marker to distinguish rat liver myofibroblasts from hepatic stellate cells. The function of other fibulins in acute or chronic liver damage has not yet been investigated. The aim of this study has been to evaluate the expression of fibulin-1 and -2 in models of rat liver injury and in human liver cirrhosis. Their cellular sources have also been investigated. In normal rat liver, fibulin-1 and -2 were both mainly present in the portal field. Fibuli...

  15. New Strategies for Acute Liver Failure: Focus on Xenotransplantation Therapy

    Alves, Luiz Anastácio; Bonavita, André; Quaresma, Kátia; Torres, Elenilde; Pacheco, Paulo Anastácio Furtado; Cotta-de-Almeida, Vinícius; Saraiva, Roberto Magalhães

    2010-01-01

    Acute liver failure (ALF) has a poor prognosis and, despite intensive care support, reported average survival is only 10–40%. The most common causes responsible for ALF are viral hepatitis (mainly hepatitis A and B) and acetaminophen poisoning. Hepatic transplantation is the only appropriate treatment for patients with unlikely survival with supportive care alone. Survival rates after transplantation can be as high as 80–90% at the end of the first year. However, there is a shortage of donors and is not uncommon that no appropriate donor matches with the patient in time to avoid death. Therefore, new technologies are in constant development, including blood purification therapies as plasmapheresis, hemodiafiltration, and bioartificial liver support. However, they are still of limited efficacy or at an experimental level, and new strategies are welcome. Accordingly, cell transplantation has been developed to serve as a possible bridge to spontaneous recovery or liver transplantation. Xenotransplant of adult hepatocytes offers an interesting alternative. Moreover, the development of transgenic pigs with less immunogenic cells associated with new immunosuppressor strategies has allowed the development of this area. This article reviews some of the newly developed techniques, with focus on xenotransplant of adult hepatocytes, which might have clinical benefits as future treatment for ALF. PMID:26998396

  16. Contribution of Transjugular Liver Biopsy in Patients with the Clinical Presentation of Acute Liver Failure

    Purpose. Acute liver failure (ALF) treated with conservative therapy has a poor prognosis, although individual survival varies greatly. In these patients, the eligibility for liver transplantation must be quickly decided. The aim of this study was to assess the role of transjugular liver biopsy (TJLB) in the management of patients with the clinical presentation of ALF. Methods. Seventeen patients with the clinical presentation of ALF were referred to our institution during a 52 month period. A TJLB was performed using the Cook Quick-Core needle biopsy. Clinical data, procedural complications, and histologic findings were evaluated. Results. Causes of ALF were virus hepatitis B infection in 7 patients, drug toxicity in 4, mushroom in 1, Wilson's disease in 1, and unknown origin in 4. TJLB was technically successful in all patients without procedure-related complications. Tissue specimens were satisfactory for diagnosis in all cases. In 14 of 17 patients the initial clinical diagnosis was confirmed by TJLB; in 3 patients the initial diagnosis was altered by the presence of unknown cirrhosis. Seven patients with necrosis <60% were successfully treated with medical therapy; 6 patients with submassive or massive necrosis (≥85%) were treated with liver transplantation. Four patients died, 3 had cirrhosis, and 1 had submassive necrosis. There was a strict statistical correlation (r = 0.972, p < 0.0001) between the amount of necrosis at the frozen section examination and the necrosis found at routine histologic examination. The average time for TJLB and frozen section examination was 80 min. Conclusion. In patients with the clinical presentation of ALF, submassive or massive liver necrosis and cirrhosis are predictors of poor prognosis. TLJB using an automated device and frozen section examination can be a quick and effective tool in clinical decision-making, especially in deciding patient selection and the best timing for liver transplantation

  17. Prognosis and Biomarkers in Acute-on-Chronic Liver Failure.

    Mookerjee, Rajeshwar P

    2016-05-01

    As formal definitions of acute-on-chronic liver failure (ACLF) have now been established, and given an increased recognition of the dynamic nature of this condition, there is a growing clinical need to assess prognosis and response to interventions. Conventional scoring systems such as Model for End-Stage Liver Disease (MELD) fail to capture the two key prognostic elements in ACLF-namely, extrahepatic organ failure and measures of systemic inflammation-and as such are limited in their prognostic accuracy. Even the best available scoring systems such as the recently described CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score, are at best 75% accurate and need to be applicable to all etiologies of liver disease. Thus, in the absence of "gold standard" markers of prognosis that render one scoring system superior to another, there is a need to explore other markers of pathophysiology that may better define outcome. This review addresses the evidence for markers of oxidative stress, including those reflecting the inflammasome; elements of cell death such as cytokeratins M30 and M65; and indicators of immune dysfunction, innate immune failure and gut dysbiosis. Finally, evidence for relevance of markers of organ dysfunction, including hemodynamic response, are explored along with associated mediators such as copeptin, dimethylarginines, and renin. It is anticipated that further critique and validation of emerging and relevant biomarkers will facilitate a composite score which, either alone or in combination with existing scoring systems such as CLIF-C, will enable improved prognostication and targeting of therapy in ACLF. PMID:27172354

  18. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  19. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases

    Almdal, T; Schroeder, T; Ranek, L

    1989-01-01

    the patients, without any differences between patients with acute or chronic liver diseases or the different degrees of hepatic encephalopathy. In conclusion, a marked reduction of the CBF was seen in hepatic encephalopathy, irrespective of the etiology of the disease.......The purpose of the present investigation was to study changes in cerebral blood flow (CBF) in hepatic encephalopathy, to ascertain whether this was related to the changes in liver function and whether these changes gave any prognostic information. CBF, determined by the intravenous xenon-133 method......, and liver functions, assessed by the prothrombin index, bilirubin concentration, and the galactose elimination capacity, were studied in patients with acute fulminant liver failure and in patients with encephalopathy due to chronic liver diseases--that is, cirrhosis of various etiologies. The CBF...

  20. Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis.

    Amir, Achiya Z; Ling, Simon C; Naqvi, Ahmed; Weitzman, Sheila; Fecteau, Annie; Grant, David; Ghanekar, Anand; Cattral, Mark; Nalli, Nadya; Cutz, Ernest; Kamath, Binita; Jones, Nicola; De Angelis, Maria; Ng, Vicky; Avitzur, Yaron

    2016-09-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD. PMID:27216884

  1. 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

    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

  2. Intracranial Pressure Monitoring in Acute Liver Failure: Institutional Case Series.

    Maloney, Patrick R; Mallory, Grant W; Atkinson, John L D; Wijdicks, Eelco F; Rabinstein, Alejandro A; Van Gompel, Jamie J

    2016-08-01

    Acute liver failure (ALF) has been associated with cerebral edema and elevated intracranial pressure (ICP), which may be managed utilizing an ICP monitor. The most feared complication of placement is catastrophic intracranial hemorrhage in the setting of severe coagulopathy. Previous studies reported hemorrhage rates between 3.8-22 % among various devices, with epidural catheters having lower hemorrhage rates and precision relative to subdural bolts and intraparenchymal catheters. We sought to identify institutional hemorrhagic rates of ICP monitoring in ALF and its associated factors in a modern series guided by protocol implantation. Patient records treated for ALF with ICP monitoring at Mayo Clinic in Rochester, MN from 1995 to 2014 were reviewed. Protocalized since 1995, epidural (EP) ICP monitors were first used followed by intraparenchymal (IP) for stage III-IV hepatic encephalopathy. The following variables and outcomes were collected: patient demographics, ICPs and treatment methods, laboratory data, imaging studies, number of days for ICP monitoring, radiographic and symptomatic hemorrhage rates, orthotopic liver transplantation rates, and death. A total of 20 ICP monitors were placed for ALF, 7 EP, and 13 IP. International normalized ratio (INR) at placement of an EP monitor was 2.4 (1.7-3.2) with maximum of 2.7 (2.0-3.6) over the following 2.3 (1-3) days. Mean EP ICP at placement was 36.3 (11-55) and maximum of 43.1 (20-70) mm Hg. INR at placement of an IP monitor was 1.3 (hepatic encephalopathy. Monitored patients in both groups experienced elevations of ICP in the setting of intermittent coagulopathy. Severity of coagulopathy did not influence hemorrhage rate. Yet, hemorrhages related to IP monitoring can be catastrophic and may add to the overall mortality. PMID:26966022

  3. Modulation of the Colonic Bacterial Flora Affects Differently Bacterial Translocation and Liver Injury in an Acute Liver Injury Model

    Adawi, Diya; Molin, Göran; Ahrné, Siv; Jeppsson, Bengt

    2011-01-01

    Objective: To evaluate the effects of the administration of different bacterial strains on the extent of liver injury and bacterial translocation in an acute liver injury model. Design: Experimental study. Setting: University hospital, Sweden. Subjects: Sprague–Dawley rats. Interventions: Six different bacterial strains (Bacteroides fragilis ATCC 25285T, Enterococcus faecium No.1, Enterococcus faecium No.2, Escherichia coli F131, Lactobacillus plantarum DSM 6595, and Bifidobacterium lon...

  4. Acute liver failure secondary to khat (Catha edulis)-induced necrotic hepatitis requiring liver transplantation: case report.

    Roelandt, P; George, C; d'Heygere, F; Aerts, R; Monbaliu, D; Laleman, W; Cassiman, D; Verslype, C; van Steenbergen, W; Pirenne, J; Wilmer, A; Nevens, F

    2011-11-01

    We describe the case of a 26-year-old man with acute liver failure secondary to ingestion of khat (Catha edulis) leaves. In fact, this is the first case of acute liver failure due to khat reported outside the United Kingdom. The combination of specific epidemiologic data (young man of East African origin) and clinical features (central nervous system stimulation, withdrawal reactions, toxic autoimmune-like hepatitis) led to the diagnosis. Mechanisms of action and potential side effects of khat are elaborated on. PMID:22099826

  5. Montelukast-induced acute fulminant liver failure: A case report

    ÇELİK, Mustafa; Arabul, Mahmut; Alper, Emrah; CANTÜRK, Fatih; KANDEMİR, Altay; Vatansever, Sezgin; Ünsal, Belkıs

    2012-01-01

    Drug-induced liver injury is commonly encountered in general practice and a potential complication of many medications. Hepatotoxicity associated with montelukast-induced liver injury including elevated liver tests, hepatitis and fulminant liver failure has been described with rare case reports. We present the case of a 42-year-old woman with montelukast-induced fulminant liver failure. A 42-year-old woman had been taking salbutamol inhaler and salmeterol + fluticasone inhaler for five y...

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

    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.

  7. Imaging of liver and spleen candidiasis in patients with acute leukemia

    Seino, Yasuo; Tamakawa, Y.; Kato, T.; Kimura, Y.; Miyazaki, S.; Miura, R.; Ishida, H.

    1988-01-01

    Four patients with acute leukemia were found to have candidal abscess of liver and spleen. CT and US showed hepatosplenomegaly and microabscess. These findings might be useful in diagnosis of visceral candidiasis.

  8. Imaging of liver and spleen candidiasis in patients with acute leukemia

    Four patients with acute leukemia were found to have candidal abscess of liver and spleen. CT and US showed hepatosplenomegaly and microabscess. These findings might be useful in diagnosis of visceral candidiasis. (author)

  9. Acute paranoid psychosis as sole clinical presentation of hepatic artery thrombosis after living donor liver transplantation

    Obed Aiman

    2010-02-01

    Full Text Available Abstract Background Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications. Case presentation Here we describe a case of hepatic artery thrombosis after living-donor liver transplantation which was not preceded by signs of liver failure but rather by an episode of acute psychosis. After re-transplantation the patient recovered without sequelae. Conclusion This case highlights the need to remain cautious when psychiatric disorders occur in patients after liver transplantation. The diagnostic procedures should not be restricted to medical or neurological causes of psychosis alone but should also focus vascular complications related to orthotopic liver transplantation.

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

    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

  11. Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy

    Haack, Tobias B.; Staufner, Christian; Köpke, Marlies G.; Straub, Beate K; Kölker, Stefan; Thiel, Christian; Freisinger, Peter; Barić, Ivo; McKiernan, Patrick J; Dikow, Nicola; Harting, Inga; Beisse, Flemming; Burgard, Peter; Kotzaeridou, Urania; Kühr, Joachim

    2015-01-01

    Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional...

  12. Acute paranoid psychosis as sole clinical presentation of hepatic artery thrombosis after living donor liver transplantation

    Obed Aiman; Ramadori Giuliano; Meier Volker; Goralczyk Armin D; Lorf Thomas

    2010-01-01

    Abstract Background Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications. Case presentation Here we describe a case of hepatic artery thrombosis after living-donor liver ...

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

    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.

  14. Evaluation of the Hepa Wash® treatment in pigs with acute liver failure

    Al-Chalabi, Ahmed; Matevossian, Edouard; v. Thaden, Anne-K.; Luppa, Peter; Neiss, Albrecht; Schuster, Tibor; Yang, Zejian; Schreiber, Catherine; Schimmel, Patrick; Nairz, Ewald; Perren, Aurel; Radermacher, Peter; Huber, Wolfgang; Schmid, Roland M.; Kreymann, Bernhard

    2013-01-01

    Background Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF. Methods In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6) groups. In...

  15. Evaluation of the Hepa Wash® treatment in pigs with acute liver failure

    Al-Chalabi, Ahmed; Matevossian, Edouard; v. Thaden, Anne-K.; Luppa, Peter; Neiss, Albrecht; Schuster, Tibor; Yang, Zejian; Schreiber, Catherine; Schimmel, Patrick; Nairz, Ewald; Radermacher, Peter; Huber, Wolfgang; Schmid, Roland M.; Kreymann, Bernhard; Perren, Aurel

    2013-01-01

    BACKGROUND Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF. METHODS In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6...

  16. Acute Hepatocellular Drug-Induced Liver Injury From Bupropion and Doxycycline

    Derek M Tang; Koh, Christopher; Twaddell, William S.; von Rosenvinge, Erik C; Han, Hyosun

    2015-01-01

    The management and diagnosis of drug-induced liver injury (DILI) is often challenging, particularly when patients are taking multiple medications. We present a 29-year-old African American man who presented with jaundice and malaise after starting bupropion and doxycycline 2 weeks prior. He was found to have acute hepatocellular drug-induced liver injury with autoimmune features, and made a complete recovery with prednisone. Although bupropion and doxycycline are both known to cause liver tox...

  17. Serum Hyperamylasemia as a prognostic indicator of acute viral hepatitis and cirrhosis of liver

    N. Kaur

    2014-06-01

    Full Text Available Liver disease is a condition that causes liver inflammation or tissue damage and affects liver function. Liver functions tests are abnormal in various liver diseases such as hepatitis, cirrhosis and end stage liver disease. The study of pancreatic enzymes for prognostic purpose in evolving liver disease is gaining ground and act as prognostic indicator for liver diseases. Present study has been planned to assess the serum amylase status in 50 patients of acute viral hepatitis and 50 patients of cirrhosis of liver in comparison to 50 normal healthy control subjects. Levels of serum amylase were determined by CNP- G3 kinetic method. The serum levels of amylase were significantly raised (p<0.0001 in patients compared to control group and levels were observed to be constantly increased with increased severity of liver diseases. The probable cause of variation in serum amylase enzymes in acute viral hepatitis and cirrhosis of liver is its anatomical proximity and common egress system through Ampulla of vater into the duodenum.

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

    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

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

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

    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 partia...

  20. Two-year outcomes in initial survivors with acute liver failure

    Fontana, Robert J; Ellerbe, Caitlyn; Durkalski, Valerie E;

    2015-01-01

    BACKGROUND & AIMS: The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2-year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after...... enrolment in the Acute Liver Failure Study Group (ALFSG). METHODS: Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed. RESULTS: Two-year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous...

  1. Variation of T cell subset during acute rejection after liver transplantation in rhesus monkeys

    Ran Jiang-hua; Liu Jing; Zhang Xi-bing; Zhang Sheng-ning; Wu Shu-yuan; Li Lai-bang; Li Wang; Li Li

    2014-01-01

    Abstract BACKGROUND: Looking for the early diagnosis of acute rejection indicators after liver transplantation can assess the risk after liver transplantation quickly and effectively, and T lymphocytes play the significant role in acute rejection. OBJECTIVE:To observe the relationship between acute rejection and variation of expression of T cel subset in blood after liver transplantation in rhesus monkey. METHODS: The sixteen liver transplant models in rhesus monkey which were constructed successfuly by the method of “double-cuff and one support tube” were divided into two groups randomly: experiment group (no treated by immunosuppressant in perioperative period) and control group (treated by immunosuppressant in perioperative period). Then the blood specimen and liver tissue respectively were colected at 6, 12, 24 and 72 hours after operation. The levels of alanine transferase, aspartate aminotransferase, and total bilirubin were detected with the fuly automatic biochemical analyser. The levels of CD4+/CD8+were tested by flow cytometry. The liver tissue in rhesus monkey after liver transplantation was detected by hematoxylin-eosin staining. The degree of acute rejection was evaluated by Banff Score System. RESULTS AND CONCLUSION: Acute rejection appeared in the experiment group at 12, 24, and 72 hours after liver transplantation. Levels of alanine transferase, aspartate aminotransferase, and total bilirubin were significantly higher in the experimental group than in the control group at 24 and 72 hours after transplantation (P < 0.05). The expression of CD4+/CD8+of the experiment group and control group began to rise at 6 hours after surgery, but the experiment group increased the most obvious. CD4+/CD8+ expression was significantly greater in the experimental group than in the control group at 24 and 72 hours after transplantation (P < 0.05). Morphological pathology was severer, and Banff score was higher in the experiment group than in the control group at

  2.  Early initiation of MARS® dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation.

    Pillukat, Mike Hendrik; Schomacher, Tina; Baier, Peter; Gabriëls, Gert; Pavenstädt, Hermann; Schmidt, Hartmut H J

    2016-01-01

     Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation. PMID:27493118

  3. Enzyme analyses of the acute damage of liver function by LP-TAE treatment

    Objective: To evaluate the changes of enzyme for acute damage to liver function during the treatment of big hepatic carcinoma by Lipiodol-Transcatheter Arterial Embolization (LP-TAE) and analyze the influence to acute liver function change concerned with different doses of Lipiodol (LP). Methods: 30 patients of big hepatic carcinoma diagnosed by CT, MRI, DSA etc. were collected with the venous blood samples before and the third day after by Lp-TAE treatment together with analyses of the relation between the changes of enzyme and the doses of Lipiodol (LP). Results: All cases suffered from acute liver dysfunction to a greater or less extent correlative with different doses of lipiodol. Conclusions: The proper proportion of doses between lipiodol and anti-cancerous drugs should be emphasized during treatment of LP-TAE in big hepatic cancers for prevention of liver dis-function, furthermore with hope to have a rule for lipiodol dosage

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

    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. PMID:26136687

  5. Acute Hepatocellular Drug-Induced Liver Injury From Bupropion and Doxycycline.

    Tang, Derek M; Koh, Christopher; Twaddell, William S; von Rosenvinge, Erik C; Han, Hyosun

    2015-10-01

    The management and diagnosis of drug-induced liver injury (DILI) is often challenging, particularly when patients are taking multiple medications. We present a 29-year-old African American man who presented with jaundice and malaise after starting bupropion and doxycycline 2 weeks prior. He was found to have acute hepatocellular drug-induced liver injury with autoimmune features, and made a complete recovery with prednisone. Although bupropion and doxycycline are both known to cause liver toxicity, a closer inspection of the signature of liver injury and a review of prior related DILI cases assigns causality more to bupropion than doxycycline. PMID:26504884

  6. Increased Serum Phospholipase A2 Activity in Advanced Chronic Liver Disease as an Expression of the Acute Phase Response

    Mario Pirisi; Carlo Fabris; Maria Piera Panozzo; Giorgio Soardo; Pierluigi Toniutto; Ettore Bartou

    1993-01-01

    Phospholipase A2 (PLA2) modifications were investigated in patients with acute and chronic liver diseases, PLA2 variations were related to indices of liver function as well as to parameters of the acute phase response. Serum PLA2 activity modifications were f1uorimetrically measured in 105 patients affected by acute and chronic liver diseases or extra-hepatic diseases. One-way ANOV A demonstrated a significant difference among groups (F= 4.53, P

  7. Total Flavonoids from Mimosa Pudica Protects Carbon Tetrachloride -Induced Acute Liver Injury in Mice

    Zhen-qin QIU

    2015-03-01

    Full Text Available Objective: To observe the protective effect of total flavonoids from Mimosa pudica on carbon tetrachloride (CCl4-induced acute liver injury in mice. Methods: CCl4-induced acute liver injury model in mice was established. The activity of ALT and AST, the content of serum albumin (Alb and total antioxidant capacity (T-AOC were determined. The content of malondiadehyde (MDA was measured and the activity of superoxide dismutase (SOD was determined. The histopathological changes of liver were observed.Results: Compared with CCl4 modle group, each dose group of total flavonouida from Mimosa pudica couldreduced the activity of ALT and AST in mice obviously (P<0.01, indicating they had remarkably protective effect on CCl4-induced acute liver injury in mice. high and middle dose groups of total flavonouida from Mimosa pudica couldincrease the content of Alb in mice (P<0.01. Each dose group of total flavonouida from Mimosa pudica could enhance the level of T-AOC (P<0.01. each dose group of total flavonouida from Mimosa pudica could lower the content of liver homogenate MDA but enhance the activity of SOD in a dose-depended manner (P<0.01. Conclusion: Total flavones from Mimosa Pudica have obvious protective effect on CCl4-induced acute liver injury in mice.

  8. Expression and significance of SOCS3 in liver tissue of rats with severe acute pancreatitis complicated by liver injury

    Wang, Bin; Zhang, Xiao-Hua; Miao-fan YANG; Xiao-wei WU; Xu, Xiao-Bing; Mei-xia GUO; Min-li LI

    2012-01-01

    Objective  To investigate the expression and mechanism of action of suppressor of cytokine signaling 3 (SOCS3) in liver tissue of rats with experimental severe acute pancreatitis (SAP) concurring with liver injury. Methods  The rat model of SAP was reproduced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Thirty-two male SD rats were randomly assigned into 4 groups (8 each): normal control group (NC), SAP 6h, 12h, and 18h groups. The levels of serum amylase (...

  9. Inter ventional treatment of acute hepatic artery occlusion after liver transplantation

    Zhi-Wei Li; Mao-Qiang Wang; Ning-Xin Zhou; Zhe Liu; Zhi-Qiang Huang

    2007-01-01

    BACKGROUND: With the development of the associated technology, interventional treatment has become an important method for the treatment of hepatic artery occlusion in some countries. This study was undertaken to evaluate the role of interventional methods in the diagnosis and treatment of acute hepatic artery occlusion after liver transplantation. METHODS: The diagnosis and treatment of 9 cases of acute hepatic artery occlusion after liver transplantation were retrospectively analyzed. RESULTS: In 109 cases of liver transplantation, 9 were diagnosed by angiography. Among them, 7 were diagnosed by Doppler ultrasound. After transcatheter thrombolysis, the hepatic arteries were partially or totally patent again in 6 cases of hepatic artery occlusion after liver transplantation, and stent placements in the hepatic artery were performed in 5 cases. All stents proved patent and no patient required another liver transplantation. CONCLUSIONS: Angiography plays an important role in diagnosing hepatic artery complications after liver transplantation. Interventional therapy is a valuable method in the treatment of acute hepatic artery occlusion after liver transplantation.

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

    Lichtmannegger, Josef; Leitzinger, Christin; Wimmer, Ralf; Schmitt, Sabine; Schulz, Sabine; Kabiri, Yaschar; 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; Adamski, Jerzy; Sauer, Vanessa; Niemietz, Christoph; Schmidt, Hartmut H J; Merle, Uta; Gotthardt, Daniel Nils; Kroemer, Guido; Weiss, Karl Heinz; Zischka, Hans

    2016-07-01

    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

  11. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications.

    Rodrigo, Regina; Cauli, Omar; Boix, Jordi; ElMlili, Nisrin; Agusti, Ana; Felipo, Vicente

    2009-01-01

    Acute liver failure (ALF) may lead to rapid death unless the patients receive a liver for transplantation. However, the number of livers available is not enough and a number of patients die before a suitable liver is available for transplantation. The liver has a high capacity for regeneration which may allow complete recovery even in patients with severe liver failure. It would be therefore very useful to have procedures to prevent or delay the mechanisms by which ALF leads to death. These mechanisms are no well understood. Progression of ALF leads to multi-organ failure, systemic inflammatory response, hepatic encephalopathy, cerebral oedema and increased intracranial pressure, which seem the most important immediate causes of mortality in patients with ALF. A main contributor to these events is hyperammonemia, due to impaired ammonia detoxification in the liver. Acute hyperammonemia per se leads to death, which is mediated by activation of the NMDA type of glutamate receptors in brain and may be prevented by antagonists blocking these receptors. Acute liver failure also leads to hyperammonemia and excessive activation of NMDA receptors in brain which contributes to ALF-induced death. Sustained blocking of NMDA receptors by continuous administration of the antagonists MK-801 or memantine increases about twice the survival time of rats with severe ALF due to injection of 2.5g/kg of galactosamine. In rats with milder ALF due to injection of 1.5g/kg of galactosamine, blocking NMDA receptors increases the percentage of surviving rats from 23% to 62% and increases about twice the survival time of the rats which die. These data strongly support that blocking NMDA receptors would improve survival of patients with ALF, either by allowing more time for liver regeneration or to get a liver suitable for transplantation. PMID:19428814

  12. Validation of the Model for End-Stage Liver Disease Score Criteria in Urgent Liver Transplantation for Acute Flare Up of Hepatitis B.

    Lee, Wei-Chen; Lee, Ching-Song; Wang, Yu-Chao; Cheng, Chih-Hsien; Wu, Tsung-Han; Lee, Chen-Fang; Soong, Ruey-Shyang; Chang, Ming-Ling; Wu, Ting-Jung; Chou, Hong-Shiue; Chan, Kun-Ming

    2016-05-01

    Acute flare up of hepatitis B in noncirrhotic liver with rapid liver function deterioration is a critical condition. This flare up of hepatitis B may be subsided under medical treatments, otherwise urgent liver transplantation is needed. However, the necessity of urgent liver transplantation is hard to decide. In this institute, the indications of urgent liver transplantation for acute flare up of hepatitis B in noncirrhotic liver were settled according to the model for end-stage liver disease (MELD) scores: once upon MELD scores ≥35 (criterion 1) or MELD score flare up of hepatitis B virus with total bilirubin ≥17.5 mg/dL were included in this study. Among 83 patients, 20 patients met criterion 1. Five patients were transplanted and 15 patients died of liver failure with a median survival of 17 days. Fifty-one patients met criterion 2. Nineteen were transplanted, 30 patients died of liver failure with a median survival of 23.5 days, and 2 patients recovered from this critical condition. The other 12 patients did not meet criteria 1 and 2, and urgent liver transplantation was spared although 5 patients needed liver transplantation in subsequent 2 to 3 months. Therefore, the sensitivity of MELD score criteria for urgent liver transplantation was 100% and specificity was 85.7%. In conclusion, determination of urgent liver transplantation for hepatitis B with acute liver failure is crucial. MELD score criteria are valid to make a decision of urgent liver transplantation for hepatitis B patients with acute flare up and liver failure. PMID:27258492

  13. Selective plasma exchange with dialysis in patients with acute liver failure.

    Nakae, Hajime; Igarashi, Toshiko; Tajimi, Kimitaka

    2012-10-01

    Selective plasma exchange with dialysis is a blood purification therapy in which simple plasma exchange is performed using a selective membrane plasma separator while the dialysate flows out of the hollow fibers. To evaluate the effect of plasma exchange with dialysis, biochemical examination of the blood, for example, the oxidative stress regulation system and interleukin 18 levels, was performed in patients with acute liver failure. We studied four patients with acute liver failure in whom the therapy was performed (nine times in total). The degree of hepatic encephalopathy and interleukin 18 levels decreased significantly after treatment. However, total protein levels did not change significantly. The level of reactive oxygen species and total antioxidant capacity did not change significantly. Plasma exchange with dialysis may be a useful blood purification therapy in cases of acute liver failure in terms of the removal of water-soluble and albumin-bound toxins. PMID:23046372

  14. The dependablitiy between CT grade of the acute pancreatitis and CT depiction of the liver parenchymatous abnormal density of the complication of the acute pancreatitis

    Objective: To investigate the dependablitiy between CT grade of the acute pancreatitis and CT depiction of the liver parenchymatous abnormal density in complication of the acute pancreatitis. Methods: Sixty patients with the acute pancreatitis were undergone abdominal helical CT scanning. Result: Two cases with liver abnormal density were in grade A, 9 were in grade B, 13 were in grade C, 18 in grade D and E, accounting for 30.0%. Conclusion: The rate and the descriptions of the liver abnormal density are higher and more distinct when the CT grade of the acute pancreatitis is in more serious category. (authors)

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

    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.

  16. Acute liver injury associated with a newer formulation of the herbal weight loss supplement Hydroxycut.

    Araujo, James L; Worman, Howard J

    2015-01-01

    Despite the widespread use of herbal and dietary supplements (HDS), serious cases of hepatotoxicity have been reported. The popular herbal weight loss supplement, Hydroxycut, has previously been implicated in acute liver injury. Since its introduction, Hydroxycut has undergone successive transformations in its formulation; yet, cases of liver injury have remained an ongoing problem. We report a case of a 41-year-old Hispanic man who developed acute hepatocellular liver injury with associated nausea, vomiting, jaundice, fatigue and asterixis attributed to the use of a newer formulation of Hydroxycut, SX-7 Clean Sensory. The patient required hospitalisation and improved with supportive therapy. Despite successive transformations in its formulation, potential liver injury appears to remain an ongoing problem with Hydroxycut. Our case illustrates the importance of obtaining a thorough medication history, including HDS, regardless of new or reformulated product marketing efforts. PMID:25948859

  17. Acute liver injury with severe coagulopathy in marasmus caused by a somatic delusional disorder.

    Stein, Lance L; Jesudian, Arun B

    2011-01-01

    Marasmus is a severe form of protein-calorie malnutrition characterized by the depletion of fat stores, muscle wasting, and the lack of edema. In developed countries, marasmus is often the result of anorexia nervosa. Abnormal transaminases with liver synthetic dysfunction have rarely been reported with anorexia nervosa. To our knowledge, we report the first detailed case of acute liver injury with severe coagulopathy (INR > 1.5) in a patient with marasmus due to self-induced calorie restriction caused by a somatic delusional disorder. This case highlights the severity of liver injury that may occur with significant weight loss from self-induced calorie restriction and the rapid normalization of this injury with treatment. It is important for clinicians to be aware of patterns of acute liver injury in patients with severe protein-calorie malnutrition, regardless of the underlying cause. PMID:25954537

  18. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

    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.

  19. Low Levels of Blood Lipids Are Associated with Etiology and Lethal Outcome in Acute Liver Failure

    Manka, Paul; Olliges, Verena; Bechmann, Lars P.; Schlattjan, Martin; Jochum, Christoph; Treckmann, Jürgen W.; Saner, Fuat H; Gerken, Guido; Syn, Wing-Kin; Canbay, Ali

    2014-01-01

    Background/Aims 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. Methods In this retrospective single center study, we reviewed 89 consecutive ALF patients, who met the cri...

  20. Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats

    B. Tang; Qiao, H.; Meng, F.; Sun, X.

    2007-01-01

    Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats...

  1. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice

    Wolf, A.M.; Wolf, D; M.A. Avila; Moschen, A R; Berasain, C; Enrich, B. (Barbara); Rumpold, H. (Holger); Tilg, H

    2006-01-01

    BACKGROUND/AIMS: Recent reports suggest that the adipose tissue and adipokines are potent modulators of inflammation. However, there is only scarce knowledge on the functional role and regulation of endogenous adiponectin in non-fat tissues such as the liver under conditions of acute inflammation. METHODS: In the present study, we investigated adiponectin expression in healthy murine liver tissue and under inflammatory conditions in vivo. RESULTS: Adiponectin mRNA was readily detectable...

  2. Genetic or Pharmacologic Amplification of Nrf2 Signaling Inhibits Acute Inflammatory Liver Injury in Mice

    Osburn, William O.; YATES, Melinda S.; Dolan, Patrick D.; Liby, Karen T.; Sporn, Michael B.; Taguchi, Keiko; Yamamoto, Masayuki; Kensler, Thomas W.

    2008-01-01

    Oxidative stress-mediated destruction of normal parenchymal cells during hepatic inflammatory responses contributes to the pathogenesis of immune-mediated hepatitis and is implicated in the progression of acute inflammatory liver injury to chronic inflammatory liver disease. The transcription factor NF-E2-related factor 2 (Nrf2) regulates the expression of a battery of antioxidative enzymes and Nrf2 signaling can be activated by small-molecule drugs that disrupt Keap1-mediated repression of N...

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

    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) and an...... increase in cerebral blood flow while the cerebrospinal fluid volume remains constant. 3. The development of intracranial hypertension in patients with acute liver failure may be controlled by manipulation of the position, body temperature, plasma tonicity, arterial carbon dioxide tension, and arterial...

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

    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.......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....

  5. Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results

    Vag, Tibor; Krumbein, Ines; Reichenbach, Juergen R.; Lopatta, Eric; Stenzel, Martin; Kaiser, Werner A.; Mentzel, Hans-Joachim [Friedrich Schiller University Jena, Institute of Diagnostic and Interventional Radiology, Jena (Germany); Kentouche, Karim; Beck, James [Friedrich Schiller University Jena, Department of Pediatrics, Jena (Germany); Renz, Diane M. [Charite University Medicine Berlin, Department of Radiology, Campus Virchow Clinic, Berlin (Germany)

    2011-08-15

    Routine assessment of body iron load in patients with acute leukemia is usually done by serum ferritin (SF) assay; however, its sensitivity is impaired by different conditions including inflammation and malignancy. To estimate, using MRI, the extent of liver iron overload in children with acute leukemia and receiving blood transfusions, and to examine the association between the degree of hepatic iron overload and clinical parameters including SF and the transfusion iron load (TIL). A total of 25 MRI measurements of the liver were performed in 15 children with acute leukemia (mean age 9.75 years) using gradient-echo sequences. Signal intensity ratios between the liver and the vertebral muscle (L/M ratio) were calculated and compared with SF-levels. TIL was estimated from the cumulative blood volume received, assuming an amount of 200 mg iron per transfused red blood cell unit. Statistical analysis revealed good correlation between the L/M SI ratio and TIL (r = -0.67, P = 0.002, 95% confidence interval CI = -0.83 to -0.34) in patients with acute leukemia as well as between L/M SI ratio and SF (r = -0.76, P = 0.0003, 95% CI = -0.89 to -0.52). SF may reliably reflect liver iron stores as a routine marker in patients suffering from acute leukemia. (orig.)

  6. Novel management of acute or secondary biliary liver conditions using hepatically differentiated human dental pulp cells.

    Ishkitiev, Nikolay; Yaegaki, Ken; Imai, Toshio; Tanaka, Tomoko; Fushimi, Naho; Mitev, Vanyo; Okada, Mio; Tominaga, Noriko; Ono, Sachie; Ishikawa, Hiroshi

    2015-02-01

    The current definitive treatment for acute or chronic liver condition, that is, cirrhosis, is liver transplantation from a limited number of donors, which might cause complications after donation. Hence, bone marrow stem cell transplantation has been developed, but the risk of carcinogenesis remains. We have recently developed a protocol for hepatic differentiation of CD117(+) stem cells from human exfoliated deciduous teeth (SHED). In the present study, we examine whether SHED hepatically differentiated (hd) in vitro could be used to treat acute liver injury (ALI) and secondary biliary cirrhosis. The CD117(+) cell fraction was magnetically separated from SHED and then differentiated into hepatocyte-like cells in vitro. The cells were transplanted into rats with either ALI or induced secondary biliary cirrhosis. Engraftment of human liver cells was determined immunohistochemically and by in situ hybridization. Recovery of liver function was examined by means of histochemical and serological tests. Livers of transplanted animals were strongly positive for human immunohistochemical factors, and in situ hybridization confirmed engraftment of human hepatocytes. The tests for recovery of liver function confirmed the presence of human hepatic markers in the animals' blood serum and lack of fibrosis and functional integration of transplanted human cells into livers. No evidence of malignancy was found. We show that in vitro hdSHED engraft morphologically and functionally into the livers of rats having acute injury or secondary biliary cirrhosis. SHED are readily accessible adult stem cells, capable of proliferating in large numbers before differentiating in vitro. This makes SHED an appropriate and safe stem cell source for regenerative medicine. PMID:25234861

  7. Hepatitis E in liver biopsies from patients with acute hepatitis of clinically unexplained origin

    MargareteOdenthal; HeidemarieHolzmann; NadineWinkel

    2013-01-01

    Hepatitis E virus (HEV) is a small RNA virus and the infectious agent of hepatitis E that occurs worldwide either as epidemics in Asia caused by genotype 1 and 2 or as sporadic disease in industrialized countries induced by genotype 3 and 4. The frequency might be underestimated in central Europe as a cause of acute hepatitis. Therefore, we analyzed on liver biopsies, if cases of acute hepatitis with clinically unknown or obscure diagnosis were actually caused by the infection with HEV. We...

  8. HLA-G Polymorphism (rs16375) and Acute Rejection in Liver Transplant Recipients

    2014-01-01

    Background. HLA-G molecules exhibit immunomodulatory properties that can delay graft rejection. The 14 bp insertion/deletion polymorphism (INDEL) (rs16375) influences the stability of final HLA-G mRNA and its soluble isoforms. Objective. The present study aimed to investigate the possible association between this polymorphism and the incidence of acute rejection in Iranian liver transplant recipients. Methods. Different genotypes were evaluated by PCR. The patients who had acute rejection wit...

  9. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure

    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....

  10. Quercetin protects against acetaminophen-induced hepatorenal toxicity by reducing reactive oxygen and nitrogen species.

    El-Shafey, Mostafa M; Abd-Allah, Gamil M; Mohamadin, Ahmed M; Harisa, Gamaleldin I; Mariee, Amr D

    2015-03-01

    High or toxic doses of acetaminophen (APAP), a mild analgesic and antipyretic drug, can cause life-threatening hepatic and renal dysfunction. This study is designed to investigate the potential protective role of quercetin to attenuate the hepatorenal toxicity induced by a high single oral dose (3g/kg) of APAP in rats. Three main groups of Sprague-Dawley rats were used: quercetin, APAP and quercetin plus APAP-receiving animals. Corresponding control animals were also used. Interestingly, oral supplementation of quercetin (15mg/kg/day) prior to APAP intoxication dramatically reduced APAP-induced hepatorenal toxicity as evidenced by measuring serum lipid profile, total protein, urea, creatinine, ALT, AST, ALP, G-GT and liver tissue content of TC and TG. Quercetin treatment markedly prevented the generation of TBARS and PCC with substantial improvement in terms of GSH and activities of antioxidant enzymes in both liver and kidney homogenates. The relationship between quercetin and NO levels which is still a matter of debate, was also investigated. NO levels in serum, liver and kidney tissues were significantly inhibited in quercetin pre-treated animals. Furthermore, quercetin administration significantly inhibited the reduction of liver and kidney contents of ATP parcels associated with this hepatorenal toxicity. These results suggest that the protective role of quercetin in the prevention of APAP-induced hepatorenal toxicity in rats was associated with the decrease of oxidative and nitrosative stress in hepatic and renal tissues as well as its capacity to improve the mitochondrial energy production. However, clinical studies are warranted to investigate such an effect in human subjects. PMID:25547049

  11. Role of Galectin-3 in Acetaminophen-Induced Hepatotoxicity and Inflammatory Mediator Production

    Dragomir, Ana-Cristina; Sun, Richard; Mishin, Vladimir; Hall, LeRoy B.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-01-01

    Galectin-3 (Gal-3) is a β-galactoside-binding lectin implicated in the regulation of macrophage activation and inflammatory mediator production. In the present studies, we analyzed the role of Gal-3 in liver inflammation and injury induced by acetaminophen (APAP). Treatment of wild-type (WT) mice with APAP (300 mg/kg, ip) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was associated with increased hepatic expression of Gal-3 messenger RNA and protein. Im...

  12. Protective effects of Parinari curatellifolia flavonoids against acetaminophen-induced hepatic necrosis in rats

    Olaleye, Mary Tolulope; Amobonye, Ayodeji Emmannuel; Komolafe, Kayode; Akinmoladun, Afolabi Clement

    2014-01-01

    In the present study, we investigated the hepatoprotective potential of Parinari curatellifolia Planch (Chrysobalanaceae) in experimental rats in order to ascertain the validity of folkloric claims of its effectiveness in the treatment of hepatic-related disorders. Flavonoid extract of P. curatellifolia seed, PCF (10-, 20- or 30 mg/kg body weight) or silymarin (25 mg/kg), dissolved in corn oil, was administered by gavage to experimental animals once daily for 14 consecutive days before liver ...

  13. Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity.

    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 TPP significantly reduced oxidant parameter levels in the ATPG group and simultaneously increased the antioxidant parameter levels of catalase and glutathione. The histological changes were improved to almost normal hepatic structure. Moreover, TPP had nearly the same hepatoprotective effect as NAC, and there was statistically no additional benefit with NAC co-treatment. There was no statistically significant difference (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. PMID:26432613

  14.  Liver transplantation followed by autologous stem cell transplantation for acute liver failure caused by AL amyloidosis. Case report and review of the literature.

    Elnegouly, Mayada; Specht, Katja; Zoller, Heinz; Matevossian, Edouard; Bassermann, Florian; Umgelter, Andreas

    2016-01-01

     Hepatic involvement in AL amyloidosis may present as acute liver failure. Historically, liver transplantation in these cases has achieved poor outcomes due to progress of amyloidosis and non-hepatic organ damage. In the era of bortezomib treatment, the prognosis of AL amyloidosis has been markedly improved and may also result in better post-transplant outcomes. We present a case of isolated acute liver failure caused by AL amyloidosis, bridged to transplantation with bortezomib and treated with sequential orthotopic liver transplantation (OLT) and autologous stem cell transplantation. The patient is in stable remission 3 years after OLT. PMID:27236160

  15. Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

    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.

  16. Histological alterations in liver and testis of Astyanax aff. bimaculatus caused by acute exposition to zinc

    Daiane Cristina Marques dos Santos; Marli do Carmo Cupertino; Sérgio Luis Pinto da Matta; Juraci Alves de Oliveira; Jorge Abdala Dergam dos Santos

    2015-01-01

    This study investigated the effect of acute exposition to zinc (Zn) on histology of the liver and testes of yellow tail lambari (Astyanax aff. bimaculatus). The exposure consisted of six concentrations of Zn (0, 3, 5, 10, 15, and 20 mg/L) for 96 hours of exposure. Fragments of liver and testis were routinely processed and embedded in plastic resin based on glycol methacrylate. Fragments of bones, muscles, liver and testis were dehydrated and digested to quantify the absorption levels of Zn in...

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

    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...... patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a...

  18. Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation

    Kim, Nayoung; Yoon, Young-In; Yoo, Hyun Ju; Tak, Eunyoung; Ahn, Chul-Soo; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin

    2016-01-01

    Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID:27498551

  19. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans

    Harrill, Alison H.; Watkins, Paul B; Su, Stephen; Ross, Pamela K.; Harbourt, David E; Stylianou, Ioannis M; Boorman, Gary A.; Russo, Mark W.; Sackler, Richard S.; Harris, Stephen C.; Smith, Philip C.; Tennant, Raymond; Bogue, Molly; Paigen, Kenneth; Harris, Christopher

    2009-01-01

    Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies c...

  20. Hepatitis E in liver biopsies from patients with acute hepatitis of clinically unexplained origin.

    Uta eDrebber

    2013-12-01

    Full Text Available Hepatitis E virus (HEV is a small RNA virus and the infectious agent of hepatitis E that occurs worldwide either as epidemics in Asia caused by genotype 1 and 2 or as sporadic disease in industrialized countries induced by genotype 3 and 4. The frequency might be underestimated in central Europe as a cause of acute hepatitis. Therefore, we analyzed on liver biopsies, if cases of acute hepatitis with clinically unknown or obscure diagnosis were actually caused by the infection with HEV.We included 221 liver biopsies retrieved from the files of the institute of pathology during the years 2000 till 2010 that were taken from patients with acute hepatitis of obscure or doubtful diagnosis. From all biopsies RNA was extracted, prepared, and subjected to RT-PCR with specific primers. Amplified RNA was detected in 7 patients, sequenced and the genotype 3 could be determined in four of the seven of positive specimens from 221 samples. Histopathology of the biopsies revealed a classic acute hepatitis with cholestatic features and in some cases confluent necrosis in zone 3. Histology in a cohort of matched patients was less severe and showed more eosinophils. The analysis of the immune response by subtyping of liver infiltrating lymphocytes showed circumstantial evidence of adaptive immune reaction with CD 8 positive CTLs being the dominant lymphocyte population.In conclusion, in doubtful cases of acute hepatitis of unknown origine hepatitis E virus infection should be considered as etiology in central Europe. We demonstrate for the first time that the diagnosis can be made in paraffin-embedded liver biopsies reliably when no serum is available and also the genotype can be determined. The analysis of the immune response by subtyping of liver infiltrating lymphocytes indicates an adaptive mechanism suggesting in analogy with HAV, HBV and HCV that the virus itself is not cytopathic but liver damage is due to immune reaction.

  1. Severe starvation-induced hepatocyte autophagy as a cause of acute liver injury in anorexia nervosa: a case report.

    Restellini, S; Spahr, L; Rubbia Brandt, L

    2013-01-01

    Introduction. Mild elevation of transaminase may be observed in anorexia nervosa, but acute liver injury is uncommon. A complex programmed cell death in response to starvation, called autophagy, has been described in experimental and human studies. Case Presentation. A 24-year-old woman suffering from anorexia nervosa was hospitalized for severe malnutrition. At admission, there were biological signs of acute liver injury but no electrolytic imbalance. After having ruled out the most common causes of liver injury, the patient was carefully refed. As liver tests remained abnormal, liver biopsy was performed. At histology and electron microscopy, numerous signs suggestive of starvation-induced hepatocyte autophagy were found. Discussion. Severe starvation can be associated with acute liver injury that is slowly reversible with careful enteral nutrition. In this clinical situation, profound hepatic glycogen depletion in association with autophagy appears as the leading cause of liver injury. PMID:25379300

  2. Role of galectin-3 in acetaminophen-induced hepatotoxicity and inflammatory mediator production.

    Dragomir, Ana-Cristina; Sun, Richard; Mishin, Vladimir; Hall, LeRoy B; Laskin, Jeffrey D; Laskin, Debra L

    2012-06-01

    Galectin-3 (Gal-3) is a β-galactoside-binding lectin implicated in the regulation of macrophage activation and inflammatory mediator production. In the present studies, we analyzed the role of Gal-3 in liver inflammation and injury induced by acetaminophen (APAP). Treatment of wild-type (WT) mice with APAP (300 mg/kg, ip) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was associated with increased hepatic expression of Gal-3 messenger RNA and protein. Immunohistochemical analysis showed that Gal-3 was predominantly expressed by mononuclear cells infiltrating into necrotic areas. APAP-induced hepatotoxicity was reduced in Gal-3-deficient mice. This was most pronounced at 48-72 h post-APAP and correlated with decreases in APAP-induced expression of 24p3, a marker of inflammation and oxidative stress. These effects were not due to alterations in APAP metabolism or hepatic glutathione levels. The proinflammatory proteins, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, macrophage inflammatory protein (MIP)-2, matrix metalloproteinase (MMP)-9, and MIP-3α, as well as the Gal-3 receptor (CD98), were upregulated in livers of WT mice after APAP intoxication. Loss of Gal-3 resulted in a significant reduction in expression of iNOS, MMP-9, MIP-3α, and CD98, with no effects on IL-1β. Whereas APAP-induced increases in MIP-2 were augmented at 6 h in Gal-3(-/-) mice when compared with WT mice, at 48 and 72 h, they were suppressed. Tumor necrosis factor receptor-1 (TNFR1) was also upregulated after APAP, a response dependent on Gal-3. Moreover, exaggerated APAP hepatotoxicity in mice lacking TNFR1 was associated with increased Gal-3 expression. These data demonstrate that Gal-3 is important in promoting inflammation and injury in the liver following APAP intoxication. PMID:22461450

  3. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    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

  4. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    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

  5. Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice.

    Cheng, Yuanming; Luo, Chunling; Wu, Wenwu; Xie, Zhiqin; Fu, Xiangdong; Feng, Ying

    2016-06-01

    The liver performs a variety of unique functions critical for metabolic homeostasis. Here, we show that mice lacking the splicing factor SRSF2 but not SRSF1 in hepatocytes have severe liver pathology and biochemical abnormalities. Histological analyses revealed generalized hepatitis with the presence of ballooned hepatocytes and evidence of fibrosis. Molecular analysis demonstrated that SRSF2 governs splicing of multiple genes involved in the stress-induced cell death pathway in the liver. More importantly, SRSF2 also functions as a potent transcription activator, required for efficient expression of transcription factors mainly responsible for energy homeostasis and bile acid metabolism in the liver. Consistent with the effects of SRSF2 in gene regulation, accumulation of total cholesterol and bile acids was prominently observed in the mutant liver, followed by enhanced generation of reactive oxygen species and increased endoplasmic reticulum stress, as revealed by biochemical and ultrastructural analyses. Taking these observations together, inactivation of SRSF2 in liver caused dysregulated splicing events and hepatic metabolic disorders, which trigger endoplasmic reticulum stress, oxidative stress, and finally liver failure. PMID:27022105

  6. Ascertainment of acute liver injury in two European primary care databases

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.; Schlienger, R.; Reynolds, R.; Klungel, O.

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods T

  7. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure

    Bañares, Rafael; Nevens, Frederik; Larsen, Fin Stolze;

    2013-01-01

    Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189...

  8. Epidemiology and Healthcare Burden of Acute-on-Chronic Liver Failure.

    Allen, Alina M; Kim, W Ray

    2016-05-01

    Chronic liver disease and cirrhosis, a common end result of viral hepatitis, alcohol abuse, and the emerging epidemic of nonalcoholic fatty liver disease are a significant source of morbidity and premature mortality globally. Acute clinical deterioration of chronic liver disease exemplifies the pinnacle of healthcare burden due to the intensive medical needs and high mortality risk. Although a uniformly accepted definition for epidemiological studies is lacking, acute-on-chronic liver failure (ACLF) is increasingly recognized as an important source of disease burden. At least in the United States, hospitalizations for ACLF have increased several fold in the last decade and have a high fatality rate. Acute-on-chronic liver failure incurs extremely high costs, exceeding the yearly costs of inpatient management of other common medical conditions. Although further epidemiological data are needed to better understand the true impact and future trends of ACLF, these data point to the urgency in the clinical investigation for ACLF and the deployment of healthcare resources for timely and effective interventions in affected patients. PMID:27172353

  9. Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

    Banwari; Agarwal; Andrew; Davenport

    2014-01-01

    Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease(MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period.

  10. Evaluation of nephroprotective, diuretic, and antioxidant activities of plectranthus amboinicus on acetaminophen-induced nephrotoxic rats.

    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. PMID:20367443