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Sample records for human acute liver

  1. Acute Liver Failure

    Science.gov (United States)

    ... can cause acute liver failure. It is an industrial chemical found in refrigerants and solvents for waxes, varnishes ... measures when spraying insecticides, fungicides, paint and other toxic chemicals. Follow product instructions carefully. Watch what gets on ...

  2. Acute liver failure

    DEFF Research Database (Denmark)

    Larsen, Fin Stolze; Bjerring, Peter Nissen

    2011-01-01

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

  3. Acute liver failure

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  4. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

    Directory of Open Access Journals (Sweden)

    Shanzheng Lu

    2016-10-01

    Full Text Available Abstract Background The endometrial regenerative cell (ERC is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4–induced acute liver injury (ALI. Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury

  5. Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

    Science.gov (United States)

    Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen

    2012-01-01

    Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. PMID:23197664

  6. Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

    OpenAIRE

    Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen; Wang, Fu-Sheng

    2012-01-01

    This study assessed the safety and initial efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusions for acute-on-chronic liver failure (ACLF) patients associated with hepatitis B virus (HBV) infection. No significant side effects were observed, and the UC-MSC transfusions significantly increased the survival rates in ACLF patients. It was found that UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients.

  7. Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury

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    Burra Patrizia

    2012-07-01

    Full Text Available Abstract Background Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs, a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model. Methods Mesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion. To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification. Data were analyzed by Mann–Whitney U-test, Kruskal-Wallis test and Cuzick’s test followed by Bonferroni correction for multiple comparisons. Results We have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However

  8. Therapeutic hypothermia for acute liver failure

    DEFF Research Database (Denmark)

    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...... insults, hypothermia reduces cerebral edema and intracranial hypertension in patients with acute liver failure by decreasing splanchnic ammonia production, restoring normal regulation of cerebral hemodynamics, and lowering oxidative metabolism within the brain. Hypothermia may also ameliorate the degree...... 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...

  9. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

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    Dan Xu

    2014-04-01

    Full Text Available Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU] developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology

  10. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

    Science.gov (United States)

    Xu, Dan; Nishimura, Toshi; Nishimura, Sachiko; Zhang, Haili; Zheng, Ming; Guo, Ying-Ying; Masek, Marylin; Michie, Sara A; Glenn, Jeffrey; Peltz, Gary

    2014-04-01

    Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve

  11. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker

  12. Acute alcohol-induced liver injury

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    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.

  13. THE DIAGNOSIS OF LIVER ALLOGRAFT ACUTE REJECTION IN LIVER BIOPSIES

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    L. V. Shkalova

    2011-01-01

    Full Text Available We performed histological examination of 80 liver allograft biopsies, the diagnosis of acute rejection was proved in 34 cases. Histological changes in liver biopsies in different grades of acute rejection were estimated according to Banff classification 1995, 1997 and were compared with current literature data. The article deals with the question of morphological value of grading acute rejection on early and late, also we analyze changes in treat- ment tactics after morphological verification of liver allograft acute rejection. 

  14. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Serum neopterin and soluble CD163 as markers of macrophage activation in paracetamol (acetaminophen)-induced human acute liver injury.

    Science.gov (United States)

    Craig, D G; Lee, P; Pryde, E A; Hayes, P C; Simpson, K J

    2013-12-01

    Macrophage activation is implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS) following paracetamol (acetaminophen) overdose (POD). Neopterin is synthesised from macrophages and reflects the intensity of monocyte/macrophage activation. Soluble CD163 (sCD163) is a marker of alternatively activated M2 macrophages. To examine neopterin and sCD163 levels in a cohort of acute liver injury patients. Consecutive patients (n = 41, (18 (43.9%) male) with acute liver injury were enrolled. Neopterin and sCD163 levels were measured by ELISA. A total of 24/33 (72.7%) POD patients developed hepatic encephalopathy (HE), and therefore acute liver failure. Both neopterin and sCD163 levels were significantly higher in PODs compared with chronic liver disease (neopterin P paracetamol overdose, and reflect the degree of macrophage activation in this condition. Serum neopterin in particular may have value as an early proxy marker of macrophage activation following paracetamol overdose. © 2013 John Wiley & Sons Ltd.

  16. FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

    DEFF Research Database (Denmark)

    Søberg, Susanna; Andersen, Emilie S; Dalgaard, Niels B

    2018-01-01

    . KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active...... plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. METHODS: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma...... correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. RESULTS: We show...

  17. Acute liver failure and self-medication

    OpenAIRE

    OLIVEIRA, André Vitorio Câmara de; 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 l...

  18. Acute renal dysfunction in liver diseases

    OpenAIRE

    Betrosian, Alex P; Agarwal, Banwari; Douzinas, Emmanuel E

    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 (HRS) is a unique form of renal failure associated with advanced liver dise...

  19. in Human Liver Diseases

    Directory of Open Access Journals (Sweden)

    Minoru Fujimoto

    2010-01-01

    Full Text Available Toll-like receptor (TLR signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

  20. Clinical heterogeneity in autoimmune acute liver failure

    Science.gov (United States)

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

    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 Médicas y Nutrición 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. PMID:17465474

  1. Acute-on-chronic Liver Failure.

    Science.gov (United States)

    Sarin, Shiv Kumar; Choudhury, Ashok

    2016-12-01

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

  2. Acute liver failure and self-medication.

    Science.gov (United States)

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

    2014-01-01

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

  3. Bridging a patient with acute liver failure to liver transplantation by the AMC-bioartificial liver

    NARCIS (Netherlands)

    van de Kerkhove, Maarten-Paul; di Florio, Ernesto; Scuderi, Vincenzo; Mancini, Antonio; Belli, Antonello; Bracco, Adele; Scala, Daniela; Scala, Simona; Zeuli, Laura; Di Nicuolo, Giuseppe; Amoroso, Pietro; Calise, Fulvio; Chamuleau, Robert A. F. M.

    2003-01-01

    Recently a phase I clinical trial has been started in Italy to bridge patients with acute liver failure (ALF) to orthotopic liver transplantation (OLT) by the AMC-bioartificial liver (AMC-BAL). The AMC-BAL is charged with 10 X 109 viable primary porcine hepatocytes isolated from a specified

  4. Acute liver failure in Cuban children.

    Science.gov (United States)

    Silverio, César E; Smithen-Romany, Chleo Y; Hondal, Norma I; Díaz, Hetzel O; Castellanos, Marlen I; Sosa, Oramis

    2015-01-01

    Acute liver failure is rare in pediatric patients and is one of the most challenging medical emergencies due to its prognostic and therapeutic implications. The best scientific evidence worldwide comes from multicenter studies in developed countries. In Cuba, there are no prior studies of this disorder in children. Describe the main clinical features of Cuban children treated at a national referral center for acute liver failure, as defined by recognized diagnostic criteria for pediatric patients. A case series study was conducted comprising patients diagnosed with acute liver failure treated from 2005 to 2011 in the hepatology and liver transplant service at Havana's William Soler University Children's Hospital. Variables were age group, etiology of acute liver failure, grade of hepatic encephalopathy, blood chemistry variables, and clinical outcome (whether or not spontaneous recovery of liver function occurred). Associations between variables were assessed using contingency tables, and case fatality was calculated, as well as relative risk with its 95% confidence interval. The Mann-Whitney U test was used to compare means of laboratory test results. Median age of the 31 patients studied (14 boys and 17 girls) was 24 months (range 1-180). Time between symptom onset and diagnosis of acute liver failure was 25.1 days (SD 16.8). Infection was the most common etiology, present in 61.3% of cases (19/31); nonhepatotropic viruses, especially cytomegalovirus, predominated in infants. Spontaneous recovery occurred in 15 patients (48.4%), 3 (9.7%) received transplants, and 13 died, for a case fatality of 41.9%. Outcome was not associated with etiology (p = 0.106), but was statistically associated with degree of hepatic encephalopathy (p failure in Cuban children calls for further epidemiologic study and identification of local underlying determinants of this phenomenon.

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

    NARCIS (Netherlands)

    Włodzimirow, K.A.

    2013-01-01

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

  6. [Brain oedema and acute liver failure].

    Science.gov (United States)

    Spahr, L

    2003-04-01

    Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

  7. Plasma osteopontin in acute liver failure

    DEFF Research Database (Denmark)

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

    2015-01-01

    BACKGROUND: Osteopontin (OPN) is a novel phosphoglycoprotein expressed in Kupffer cells that plays a pivotal role in activating natural killer cells, neutrophils and macrophages. Measuring plasma OPN levels in patients with acute liver failure (ALF) might provide insights into OPN function...... in the setting of massive hepatocyte injury. METHODS: OPN levels were measured using a Quantikine® ELISA assay on plasma from 105 consecutive ALF patients enrolled by the US Acute Liver Failure Study Group, as well as controls including 40 with rheumatoid arthritis (RA) and 35 healthy subjects both before, and 1...... 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...

  8. Acute Liver Failure Secondary to Niacin Toxicity

    Directory of Open Access Journals (Sweden)

    Marc A. Ellsworth

    2014-01-01

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

  9. ACUTE APENDICITIS IN LIVER TRANSPLANT RECIPIENTS.

    Science.gov (United States)

    Fonseca-Neto, Olival Cirilo Lucena da; Lima, Heloise Caroline de Souza; Melo, Paulo Sérgio Vieira de; Lemos, Roberto; Leitão, Laércio; Amorim, Américo Gusmão; Lacerda, Cláudio Moura

    2016-03-01

    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. To report the occurrence of acute appendicitis in a cohort of liver transplant recipients. Retrospective analysis in a period of 12 years among 925 liver transplants, in witch five cases of acute appendicitis were encountered. 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. 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.

  10. Steroid use in acute liver failure

    DEFF Research Database (Denmark)

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

    2014-01-01

    UNLABELLED: Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indete......UNLABELLED: Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug......-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS......% 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...

  11. AGE WISE HISTOMORPHOLOGICAL CHANGES IN HUMAN LIVER

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    Tribeni

    2015-11-01

    Full Text Available CONTEXT: Hepato cellular carcinoma (HCC results in between 2.5 lakhs to 1million deaths globally per annum. Liver transplantation nowadays is a well accepted treatment option for end-stage liver disease and acute liver failure. AIMS: Keeping this concept in view, a study was conducted in the Guwahati Zone of Northeast India, to compare the histomorphological features of the human liver in different age groups. SETTING AND DESIGN: Apparently healthy livers were obtained from 21 subjects on whom medicolegal post-mortems had been performed. Their ages varied from newborn to 90 years. Subjects were divided into 3 groups. 7 specimens were taken from each group. (1 Pediatric (2 Adult (3 Old age. METHODS AND MATERIALS: In all the above age groups, immediately after removal of the livers, they were washed in normal saline, dried with blotting paper and weighed in an electronic weighing machine. Sections of liver were fixed, processed, cut and stained with Harris Haematoxylin and Eosin stain. RESULTS: The liver loses weight from 50 years onwards. There appears to be racial and environmental differences in the change in liver weight in old age. Autopsy studies show a diminution of nearly 46% in liver weight between the 3rd and 10th decades of life. The liver decreases in size with age. The hepatocytes are radially disposed in the liver lobule. They are piled up, forming a layer one cell thick (except in young children in a fashion similar to the bricks of a wall. These plates are directed from the periphery of the lobule to its centre and anastomose freely forming a complex labyrinthine and sponge-like structure. CONCLUSIONS: From the findings in the present study it can be concluded that: 1. Nowadays, the measurement of liver volume has gained practical use in relation to liver transplantation. 2. We have compared the histomorphology of adult liver with a child. The findings in both the groups are very similar. This feature is important, since in

  12. The 57Fe hyperfine interactions in iron storage proteins in liver and spleen tissues from normal human and two patients with mantle cell lymphoma and acute myeloid leukemia: a Mössbauer effect study

    International Nuclear Information System (INIS)

    Oshtrakh, M. I.; Alenkina, I. V.; Vinogradov, A. V.; Konstantinova, T. S.; Semionkin, V. A.

    2015-01-01

    Study of human spleen and liver tissues from healthy persons and two patients with mantle cell lymphoma and acute myeloid leukemia was carried out using Mössbauer spectroscopy with a high velocity resolution. Small variations in the 57 Fe hyperfine parameters for normal and patient’s tissues were detected and related to small variations in the 57 Fe local microenvironment in ferrihydrite cores. The differences in the relative parts of more crystalline and more amorphous core regions were also supposed for iron storage proteins in normal and patients’ spleen and liver tissues

  13. The 57Fe hyperfine interactions in iron storage proteins in liver and spleen tissues from normal human and two patients with mantle cell lymphoma and acute myeloid leukemia: a Mössbauer effect study

    Science.gov (United States)

    Oshtrakh, M. I.; Alenkina, I. V.; Vinogradov, A. V.; Konstantinova, T. S.; Semionkin, V. A.

    2015-04-01

    Study of human spleen and liver tissues from healthy persons and two patients with mantle cell lymphoma and acute myeloid leukemia was carried out using Mössbauer spectroscopy with a high velocity resolution. Small variations in the 57Fe hyperfine parameters for normal and patient's tissues were detected and related to small variations in the 57Fe local microenvironment in ferrihydrite cores. The differences in the relative parts of more crystalline and more amorphous core regions were also supposed for iron storage proteins in normal and patients' spleen and liver tissues.

  14. The {sup 57}Fe hyperfine interactions in iron storage proteins in liver and spleen tissues from normal human and two patients with mantle cell lymphoma and acute myeloid leukemia: a Mössbauer effect study

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I., E-mail: oshtrakh@gmail.com; Alenkina, I. V. [Ural Federal University, Department of Physical Techniques and Devices for Quality Control, Institute of Physics and Technology (Russian Federation); Vinogradov, A. V.; Konstantinova, T. S. [Ural State Medical University (Russian Federation); Semionkin, V. A. [Ural Federal University, Department of Physical Techniques and Devices for Quality Control, Institute of Physics and Technology (Russian Federation)

    2015-04-15

    Study of human spleen and liver tissues from healthy persons and two patients with mantle cell lymphoma and acute myeloid leukemia was carried out using Mössbauer spectroscopy with a high velocity resolution. Small variations in the {sup 57}Fe hyperfine parameters for normal and patient’s tissues were detected and related to small variations in the {sup 57}Fe local microenvironment in ferrihydrite cores. The differences in the relative parts of more crystalline and more amorphous core regions were also supposed for iron storage proteins in normal and patients’ spleen and liver tissues.

  15. Etiology of pediatric acute liver failure

    Directory of Open Access Journals (Sweden)

    GUO Jing

    2017-10-01

    Full Text Available Pediatric acute liver failure (PALF is a complex syndrome with rapid progression, and the cause of PALF is age-dependent. This article analyzes the common causes of PALF in clinical practice, including infection factors, inherited metabolic factors, poisoning and drugs, abnormal perfusion, and autoimmune diseases, among which infection factors are the most common cause. With the improvement in diagnosis and treatment techniques, the diagnostic rate of PALF caused by inherited metabolic diseases and autoimmune diseases keeps increasing. Due to the small number of PALF patients, there lacks experience in etiological diagnosis. This article summarizes related reports, in order to provide a reference for screening the causes of PALF.

  16. Living Donor Liver Transplantation for Acute Liver Failure : Comparing Guidelines on the Prediction of Liver Transplantation.

    Science.gov (United States)

    Yoshida, Kazuhiro; Umeda, Yuzo; Takaki, Akinobu; Nagasaka, Takeshi; Yoshida, Ryuichi; Nobuoka, Daisuke; Kuise, Takashi; Takagi, Kosei; Yasunaka, Tetsuya; Okada, Hiroyuki; Yagi, Takahito; Fujiwara, Toshiyoshi

    2017-10-01

    Determining the indications for and timing of liver transplantation (LT) for acute liver failure (ALF) is essential. The King's College Hospital (KCH) guidelines and Japanese guidelines are used to predict the need for LT and the outcomes in ALF. These guidelines' accuracy when applied to ALF in different regional and etiological backgrounds may differ. Here we compared the accuracy of new (2010) Japanese guidelines that use a simple scoring system with the 1996 Japanese guidelines and the KCH criteria for living donor liver transplantation (LDLT). We retrospectively analyzed 24 adult ALF patients (18 acute type, 6 sub-acute type) who underwent LDLT in 1998-2009 at our institution. We assessed the accuracies of the 3 guidelines' criteria for ALF. The overall 1-year survival rate was 87.5%. The new and previous Japanese guidelines were superior to the KCH criteria for accurately predicting LT for acute-type ALF (72% vs. 17%). The new Japanese guidelines could identify 13 acute-type ALF patients for LT, based on the timing of encephalopathy onset. Using the previous Japanese guidelines, although the same 13 acute-type ALF patients (72%) had indications for LT, only 4 patients were indicated at the 1st step, and it took an additional 5 days to decide the indication at the 2nd step in the other 9 cases. Our findings showed that the new Japanese guidelines can predict the indications for LT and provide a reliable alternative to the previous Japanese and KCH guidelines.

  17. Tocilizumab-Induced Acute Liver Injury in Adult Onset Still’s Disease

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    Michael Drepper

    2013-01-01

    Full Text Available Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still’s disease (AOSD. Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.

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

    Science.gov (United States)

    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.

  19. [Causes and management of severe acute liver damage during pregnancy].

    Science.gov (United States)

    Sepulveda-Martinez, Alvaro; Romero, Carlos; Juarez, Guido; Hasbun, Jorge; Parra-Cordero, Mauro

    2015-05-01

    Abnormalities in liver function tests appear in 3% of pregnancies. Severe acute liver damage can be an exclusive condition of pregnancy (dependent or independent of pre-eclampsia) or a concomitant disease. HELLP syndrome and acute fatty liver of pregnancy are the most severe liver diseases associated with pregnancy. Both appear during the third trimester and have a similar clinical presentation. Acute fatty liver may be associated with hypoglycemia and HELLP syndrome is closely linked with pre-eclampsia. Among concomitant conditions, fulminant acute hepatitis caused by medications or virus is the most severe disease. Its clinical presentation may be hyper-acute with neurological involvement and severe coagulation disorders. It has a high mortality and patients should be transplanted. Fulminant hepatic failure caused by acetaminophen overdose can be managed with n-acetyl cysteine. Because of the high fetal mortality rate, the gestational age at diagnosis is crucial.

  20. Endothelial-astrocytic interactions in acute liver failure.

    Science.gov (United States)

    Jayakumar, A R; Norenberg, M D

    2013-06-01

    Brain edema and the subsequent increase in intracranial pressure are major neurological complications of acute liver failure (ALF), and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in ALF. Recent studies, however, have suggested the co-existence of cytotoxic and vasogenic mechanisms in the brain edema associated with ALF. This review 1) summarizes the nature of the brain edema in humans and experimental animals with ALF; 2) reviews in vitro studies supporting the presence of cytotoxic brain edema (cell swelling in cultured astrocytes); and 3) documents the role of brain endothelial cells in the development of astrocyte swelling/brain edema in ALF.

  1. Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

    Science.gov (United States)

    Lee, Karla C L; Baker, Luisa A; Stanzani, Giacomo; Alibhai, Hatim; Chang, Yu Mei; Jimenez Palacios, Carolina; Leckie, Pamela J; Giordano, Paola; Priestnall, Simon L; Antoine, Daniel J; Jenkins, Rosalind E; Goldring, Christopher E; Park, B Kevin; Andreola, Fausto; Agarwal, Banwari; Mookerjee, Rajeshwar P; Davies, Nathan A; Jalan, Rajiv

    2015-09-01

    In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Geneviève Tessier

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Saner FH

    2009-12-01

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

  4. Outcome of acute liver failure in the elderly

    DEFF Research Database (Denmark)

    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...

  5. Mice with humanized liver endothelium

    NARCIS (Netherlands)

    el Filali, E.

    2014-01-01

    The only curative treatment option for a large proportion of patients suffering from a liver disorder is liver transplantation. The use of ex vivo genetically modified autologous liver cells instead of whole liver transplantation could overcome the problem of donor scarcity. Even though clinical

  6. Hepatic cholesterol ester hydrolase in human liver disease.

    Science.gov (United States)

    Simon, J B; Poon, R W

    1978-09-01

    Human liver contains an acid cholesterol ester hydrolase (CEH) of presumed lysosomal origin, but its significance is unknown. We developed a modified CEH radioassay suitable for needle biopsy specimens and measured hepatic activity of this enzyme in 69 patients undergoing percutaneous liver biopsy. Histologically normal livers hydrolyzed 5.80 +/- 0.78 SEM mumoles of cholesterol ester per hr per g of liver protein (n, 10). Values were similar in alcoholic liver disease (n, 17), obstructive jaundice (n, 9), and miscellaneous hepatic disorders (n, 21). In contrast, mean hepatic CEH activity was more than 3-fold elevated in 12 patients with acute hepatitis, 21.05 +/- 2.45 SEM mumoles per hr per g of protein (P less than 0.01). In 2 patients studied serially, CEH returned to normal as hepatitis resolved. CEH activity in all patients paralleled SGOT levels (r, 0.84; P less than 0.01). There was no correlation with serum levels of free or esterified cholesterol nor with serum activity of lecithin-cholesterol acyltransferase, the enzyme responsible for cholesterol esterification in plasma. These studies confirm the presence of CEH activity in human liver and show markedly increased activity in acute hepatitis. The pathogenesis and clinical significance of altered hepatic CEH activity in liver disease require further study.

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

    Directory of Open Access Journals (Sweden)

    Yumin Xu

    Full Text Available 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.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.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.sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  8. Montelukast induced acute hepatocellular liver injury

    Directory of Open Access Journals (Sweden)

    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. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure

    NARCIS (Netherlands)

    Lisman, T.; Bakhtiari, K.; Adelmeijer, J.; Meijers, J. C. M.; Porte, R. J.; Stravitz, R. T.

    2012-01-01

    . Background: It has been well established that hemostatic potential in patients with chronic liver disease is in a rebalanced status due to a concomitant decrease in pro- and antihemostatic drivers. The hemostatic changes in patients with acute liver injury/failure (ALI/ALF) are similar but not

  10. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure

    NARCIS (Netherlands)

    Lisman, T.; Bakhtiari, K.; Adelmeijer, J.; Meijers, J. C. M.; Porte, R. J.; Stravitz, R. T.

    . Background: It has been well established that hemostatic potential in patients with chronic liver disease is in a rebalanced status due to a concomitant decrease in pro- and antihemostatic drivers. The hemostatic changes in patients with acute liver injury/failure (ALI/ALF) are similar but not

  11. Pentose pathway in human liver

    International Nuclear Information System (INIS)

    Magnusson, I.; Chandramouli, V.; Schumann, W.C.; Kumaran, K.; Wahren, J.; Landau, B.R.

    1988-01-01

    [1- 14 C]Ribose and [1- 14 C]glucose were given to normal subjects along with glucose loads (1 g per kg of body weight) after administration of diflunisal and acetaminophen, drugs that are excreted in urine as glucuronides. Distributions of 14 C were determined in the carbons of the excreted glucoronides and in the glucose from blood samples drawn from hepatic veins before and after glucagon administration. Eighty percent or more of the 14 C from [1- 14 C]ribose incorporated into the glucuronic acid moiety of the glucuronides was in carbons 1 and 3, with less than 8% in carbon 2. In glucuronic acid from glucuronide excreted when [2- 14 C]glucose was given, 3.5-8.1% of the 14 C was in carbon 1, 2.5-4.3% in carbon 3, and more than 70% in carbon 2. These distributions are in accord with the glucuronides sampling the glucose unit of the glucose 6-phosphate pool that is a component of the pentose pathway and is intermediate in glycogen formation. It is concluded that the glucuronic acid conjugates of the drugs can serve as a noninvasive means of sampling hepatic glucose 6-phosphate. In human liver, as in animal liver, the classical pentose pathway functions, not the L-type pathway, and only a small percentage of the glucose is metabolized via the pathway

  12. Advances in the treatment of acute liver failure

    Directory of Open Access Journals (Sweden)

    LUO Ling

    2018-02-01

    Full Text Available Acute liver failure (ALF is a rare life-threatening disease with rapid progression and a low survival rate and affects the function of multiple organ systems. Early identification of cause and protection of vital organs are critical for patients' survival. With the development in artificial liver, stem cell transplantation, and liver transplantation in recent years, the outcome of ALF has been greatly improved. This article elaborates on the treatment of ALF from the aspects of the etiology of ALF and major organ systems involved and introduces the latest advances in artificial liver and stem cell transplantation.

  13. Yogi Detox Tea: A Potential Cause of Acute Liver Failure.

    Science.gov (United States)

    Kesavarapu, Keerthana; Kang, Mitchell; Shin, Jaewook James; Rothstein, Kenneth

    2017-01-01

    We present a case of acute fulminant liver failure from a liver detoxification tea. We present a 60-year-old female with weakness, lethargy, scleral icterus, jaundice, and worsening mental status. She drank herbal tea three times a day for 14 days prior to symptom development. Liver tests were elevated. Remaining laboratory tests and imaging were negative for other etiologies. An ultrasound-guided liver biopsy showed submassive necrosis. A literature search on the ingredients shows six ingredients as having hepatotoxic effects and remaining ingredients as having very sparse hepatoprotective data. Healthcare professionals should discuss herbal medication and tea use and report adverse effects.

  14. Yogi Detox Tea: A Potential Cause of Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Keerthana Kesavarapu

    2017-01-01

    Full Text Available We present a case of acute fulminant liver failure from a liver detoxification tea. We present a 60-year-old female with weakness, lethargy, scleral icterus, jaundice, and worsening mental status. She drank herbal tea three times a day for 14 days prior to symptom development. Liver tests were elevated. Remaining laboratory tests and imaging were negative for other etiologies. An ultrasound-guided liver biopsy showed submassive necrosis. A literature search on the ingredients shows six ingredients as having hepatotoxic effects and remaining ingredients as having very sparse hepatoprotective data. Healthcare professionals should discuss herbal medication and tea use and report adverse effects.

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

    International Nuclear Information System (INIS)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

    2013-01-01

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients.

    Science.gov (United States)

    Fan, Hua; Li, Li-Xin; Han, Dong-Dong; Kou, Jian-Tao; Li, Ping; He, Qiang

    2012-12-15

    Although many human inflammatory and autoimmune diseases were previously considered to be mediated by T helper type 1 (Th1) cells, the recently described Th17 cells play dominant roles in several of these diseases. We and others speculated that allograft rejection after organ transplantation may also involve Th17 cells. Episodes of acute rejection occur in 30% of liver transplants. This study aimed to determine the frequency of circulating Th17 cells in patients who had received liver transplants for benign end-stage liver disease and to identify any association between acute rejection episodes and levels of Th17 cells in the peripheral blood. A prospective study compared Th17 cells from 76 consecutive benign end-stage liver disease patients who had undergone orthotopic liver transplantation from 2007 to 2011 with those from 20 age-matched healthy individuals. Peripheral blood samples were collected at different time points within one year after transplant. Blood samples and liver biopsies were also collected at the diagnosis of acute rejection. Percentages of circulating CD4+IL-17+ cells were measured by flow cytometry. The transplant patients were classified into two groups: a rejection group consisting of 17 patients who had an episode of acute rejection, and a non-rejection group comprising the remaining 59 patients with no acute rejection episodes. Percentages of circulating Th17 cells were compared between the two groups and controls. The levels of circulating CD4+IL-17+ T cells in the rejection group were higher during acute rejection than those in the non-rejection group (2.56+/-0.43% versus 1.79+/-0.44%, Pblood was positively correlated with the rejection activity index (r=0.79, P=0.0002). Circulating Th17 cells may be useful as a surrogate marker for predicting acute rejection in liver transplant recipients.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Experimental models of hepatotoxicity related to acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Maes, Michaël [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Vinken, Mathieu, E-mail: mvinken@vub.ac.be [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City (United States)

    2016-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.

  20. Entamoeba histolytica acetyl–CoA synthetase: biomarker of acute amoebic liver abscess

    Directory of Open Access Journals (Sweden)

    Lim Boon Huat

    2014-06-01

    Conclusions: This finding suggested the significant role of EhACS as a biomarker for moribund hamsters with acute amoebic liver abscess (ALA infection. It is deemed pertinent that future studies explore the potential roles of EhACS in better understanding the pathogenesis of ALA; and in the development of vaccine and diagnostic tests to control ALA in human populations.

  1. [Establishment of a D-galactosamine/lipopolysaccharide induced acute-on-chronic liver failure model in rats].

    Science.gov (United States)

    Liu, Xu-hua; Chen, Yu; Wang, Tai-ling; Lu, Jun; Zhang, Li-jie; Song, Chen-zhao; Zhang, Jing; Duan, Zhong-ping

    2007-10-01

    To establish a practical and reproducible animal model of human acute-on-chronic liver failure for further study of the pathophysiological mechanism of acute-on-chronic liver failure and for drug screening and evaluation in its treatment. Immunological hepatic fibrosis was induced by human serum albumin in Wistar rats. In rats with early-stage cirrhosis (fibrosis stage IV), D-galactosamine and lipopolysaccharide were administered. Mortality and survival time were recorded in 20 rats. Ten rats were sacrificed at 4, 8, and 12 hours. Liver function tests and plasma cytokine levels were measured after D-galactosamine/lipopolysaccharide administration and liver pathology was studied. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Most of the rats treated with human albumin developed cirrhosis and fibrosis, and 90% of them died from acute liver failure after administration of D-galactosamine/lipopolysaccharide, with a mean survival time of (16.1+/-3.7) hours. Liver histopathology showed massive or submassive necrosis of the regenerated nodules, while fibrosis septa were intact. Liver function tests were compatible with massive necrosis of hepatocytes. Plasma level of TNFalpha increased significantly, parallel with the degree of the hepatocytes apoptosis. Plasma IL-10 levels increased similarly as seen in patients with acute-on-chronic liver failure. We established an animal model of acute-on-chronic liver failure by treating rats with human serum albumin and later with D-galactosamine and lipopolysaccharide. TNFalpha-mediated liver cell apoptoses plays a very important role in the pathogenesis of acute liver failure.

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

    DEFF Research Database (Denmark)

    Trebicka, J.

    2016-01-01

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

  3. Systematic review of severe acute liver injury caused by terbinafine.

    Science.gov (United States)

    Yan, Jun; Wang, Xiaolin; Chen, Shengli

    2014-08-01

    Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is the preferred drug to treat onychomycosis. However, severe acute hepatitis from oral terbinafine administration has been recently reported. To describe a representative case, and review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine. The literature was searched for publications on severe hepatitis caused by terbinafine using MEDLINE, China Biology Medicine Disc, and the VIP Medical Information Resource System. Related references were searched manually. Seventeen English and three Chinese references of case reports were included after eliminating duplicate publications. No randomized control studies were found. Liver enzyme levels were found to have been increased significantly. Abdominal ultrasound demonstrated cholestasis. Severe acute liver injury is a known, but unusual complication of terbinafine exposure. The prognosis is often good with appropriate treatment. Liver function assessment before treatment and periodic monitoring 4-6 weeks after initiation of treatment is recommended.

  4. Human immunodeficiency virus infection and the liver.

    Science.gov (United States)

    Crane, Megan; Iser, David; Lewin, Sharon R

    2012-03-27

    Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.

    Directory of Open Access Journals (Sweden)

    James A Richards

    Full Text Available Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury. Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66, despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/- mice (p<0.001, but not B cell deficient (μMT mice (p = 0.93, were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key

  7. [The catalase inhibitor aminotriazole alleviates acute alcoholic liver injury].

    Science.gov (United States)

    Ai, Qing; Ge, Pu; Dai, Jie; Liang, Tian-Cai; Yang, Qing; Lin, Ling; Zhang, Li

    2015-02-25

    In this study, the effects of catalase (CAT) inhibitor aminotriazole (ATZ) on alcohol-induced acute liver injury were investigated to explore the potential roles of CAT in alcoholic liver injury. Acute liver injury was induced by intraperitoneal injection of alcohol in Sprague Dawley (SD) rats, and various doses of ATZ (100-400 mg/kg) or vehicle were administered intraperitoneally at 30 min before alcohol exposure. After 24 h of alcohol exposure, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in plasma were determined. The degree of hepatic histopathological abnormality was observed by HE staining. The activity of hepatic CAT, hydrogen peroxide (H₂O₂) level and malondialdehyde (MDA) content in liver tissue were measured by corresponding kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma were determined by ELISA method. The results showed that treatment with ATZ dose-dependently suppressed the elevation of ALT, AST and LDH levels induced by alcohol exposure, and that ATZ alleviated alcohol-induced histopathological alterations. Furthermore, ATZ inhibited the activity of CAT, reduced hepatic levels of H₂O₂and MDA in alcohol exposed rats. ATZ also decreased the levels of plasma TNF-α and IL-6 in rats with alcohol exposure. These results indicated that ATZ attenuated alcohol-induced acute liver injury in rats, suggesting that CAT might play important pathological roles in the pathogenesis of alcoholic liver injury.

  8. Celiac artery trunk thrombosis presenting as acute liver failure

    International Nuclear Information System (INIS)

    Akbarian, M.A.; Kahrom, M.; Kahrom, H.

    2011-01-01

    Acute mesenteric ischemia is a life-threatening vascular emergency that requires early diagnosis and intervention to adequately restore mesenteric blood flow and to prevent bowel necrosis and patient death. While, almost always superior and inferior mesenteric arteries are involved, we report a 57-year-old male with an unusual celiac artery trunk thrombosis leading to gastero-duodenal and hepato-splenic infarction, and presenting an acute liver failure. (author)

  9. A case of acute liver failure in dengue hemorrhagic fever

    Directory of Open Access Journals (Sweden)

    Rama Biswas

    2013-07-01

    Full Text Available Dengue is an arboviral disease endemic in many parts of the world. The clinical presentation of dengue viral infection ranges from asymptomatic illness to fatal dengue shock syndrome. Although, it is known to cause hepatic involvement, it occasionally results in acute hepatic failure. We report a case of dengue hemorrhagic fever presenting with acute liver failure. The case recovered completely after treatment. Ibrahim Med. Coll. J. 2013; 7(2: 41-42

  10. Clinical observation on the treatment of acute liver failure by combined non-biological artificial liver.

    Science.gov (United States)

    Li, Maoqin; Sun, Jingxi; Li, Jiaqiong; Shi, Zaixiang; Xu, Jiyuan; Lu, Bo; Cheng, Shuli; Xu, Yanjun; Wang, Xiaomeng; Zhang, Xianjiang

    2016-12-01

    The clinical efficacy and safety of different combinations of non-bio artificial liver in the treatment of acute liver failure was examined. A total of 61 cases were selected under blood purification treatment from the patients with severe acute liver failure admitted to the severe disease department of the hospital from December, 2010 to December, 2015. Three types of artificial liver combinations were observed, i.e., plasma exchange plus hemoperfusion plus continuous venovenous hemodiafiltration (PE+HP+CVVHDF), PE+CVVHDF and HP+CVVHDF. The heart rate (HR), mean arterial pressure (MAP), respiratory index (PaO 2 /FiO 2 ), liver and kidney function indicator, as well as platelet and coagulation function were compared. A comparison before and after the treatment using the three methods, showed improvement in the HRs, MAPs, PaO 2 /FiO 2 , total bilirubins (TBIL) and alanine aminotransferases (ALT) (Prate of 62.3% (38/61), and a viral survival rate of 35.0% (7/20); with the non-viral survival rate being 75.6% (31/41). In conclusion, following the treatment of three types of artificial livers, the function was improved to varying degrees, with the PE+HP+CVVHDF and the PE+CVVHDF method being better. By contrast, after the treatment of non-viral liver failure, the survival rate was significantly higher than the patients with viral liver failure.

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

    NARCIS (Netherlands)

    Ceelie, Ilse; James, Laura P.; Gijsen, Violette; Mathot, Ron A. A.; Ito, Shinya; Tesselaar, Coranne D.; Tibboel, Dick; Koren, Gideon; de Wildt, Saskia N.

    2011-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  13. Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

    NARCIS (Netherlands)

    Nibourg, Geert A. A.; Chamuleau, Robert A. F. M.; van der Hoeven, Tessa V.; Maas, Martinus A. W.; Ruiter, An F. C.; Lamers, Wouter H.; Oude Elferink, Ronald P. J.; van Gulik, Thomas M.; Hoekstra, Ruurdtje

    2012-01-01

    A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into

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

    Science.gov (United States)

    Lee, Guan-Huei

    2015-10-01

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

  15. Comparative Study of Human Liver Ferritin and Chicken Liver by Moessbauer Spectroscopy. Preliminary Results

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I. [Ural State Technical University - UPI, Division of Applied Biophysics, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University - UPI, Faculty of Experimental Physics (Russian Federation); Prokopenko, P. G. [Russian State Medical University, Faculty of Biochemistry (Russian Federation); Malakheeva, L. I. [Simbio Holding, Science Consultation Department (Russian Federation)

    2004-12-15

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Moessbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Moessbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  16. Comparative Study of Human Liver Ferritin and Chicken Liver by Moessbauer Spectroscopy. Preliminary Results

    International Nuclear Information System (INIS)

    Oshtrakh, M. I.; Milder, O. B.; Semionkin, V. A.; Prokopenko, P. G.; Malakheeva, L. I.

    2004-01-01

    A comparative study of normal human liver ferritin and livers from normal chicken and chicken with Marek disease was made by Moessbauer spectroscopy. Small differences of quadrupole splitting and isomer shift were found for human liver ferritin and chicken liver. Moessbauer parameters for liver from normal chicken and chicken with Marek disease were the same.

  17. Case Report: Acute Fatty Liver Of Pregnancy In A 30-year Old ...

    African Journals Online (AJOL)

    Acute fatty liver of pregnancy is an uncommon, potentially fatal disorder that usually occurs in the third trimester of pregnancy or in the early post partum. We present here a 30-year-old Nigerian primigravida with acute fatty liver of pregnancy. She was successfully managed and discharged. Keywords: Acute fatty liver of ...

  18. Manipulation of nitric oxide in an animal model of acute liver injury ...

    African Journals Online (AJOL)

    We evaluated the impact of altering nitric oxide release on acute liver injury, the associated gut injury and bacterial translocation, at different time intervals. Methods: An acute rat liver injury model induced by D-galactosamine was used. Sprague Dawley rats were divided into four main groups: normal control, acute liver ...

  19. Acute liver allograft antibody-mediated rejection: an inter-institutional study of significant histopathological features.

    Science.gov (United States)

    O'Leary, Jacqueline G; Michelle Shiller, S; Bellamy, Christopher; Nalesnik, Michael A; Kaneku, Hugo; Jennings, Linda W; Isse, Kumiko; Terasaki, Paul I; Klintmalm, Göran B; Demetris, Anthony J

    2014-10-01

    Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathological characteristics have been described, specific features that could be used (1) to make a generalizable scoring system and (2) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created training and validation cohorts of putative acute AMR and control cases from 3 high-volume liver transplant programs; these cases were evaluated blindly by 4 independent transplant pathologists. Evaluations of hematoxylin and eosin (H&E) sections were performed alone without knowledge of either serum donor-specific human leukocyte antigen alloantibody (DSA) results or complement component 4d (C4d) stains. Routine histopathological features that strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final acute antibody-mediated rejection score (aAMR score)--the sum of portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic venulitis divided by the sum of lymphocytic portal inflammation and lymphocytic venulitis--exhibited a strong correlation with severe acute AMR in the training cohort [odds ratio (OR) = 2.86, P  1.75 (sensitivity = 34%, specificity = 86%) and another that optimized sensitivity at a score > 1.0 (sensitivity = 81%, specificity = 71%). In conclusion, the routine histopathological features of the aAMR score can be used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples; however, a definitive diagnosis requires substantiation by DSA testing

  20. Acute fascioliasis with multiple liver abscesses

    NARCIS (Netherlands)

    Teichmann, D.; Grobusch, M. P.; Göbels, K.; Müller, H. P.; Koehler, W.; Suttorp, N.

    2000-01-01

    Human fascioliasis is distributed worldwide with several foci of high endemicity. Being a rare disease in Europe, we describe here a case in the initial hepatic phase of the disease. Therapeutic and, with reference to the 2 distinct stages of disease, diagnostic standards are discussed

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

    Directory of Open Access Journals (Sweden)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    International Nuclear Information System (INIS)

    Han, Ga Jin; Lee, Nam Kyung; Kim, Suk; Kim, Tae Un; Song, Sang Heon; Kim, Hyun Sung; Jo, Hong Jae

    2013-01-01

    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

  4. Acute Liver Failure among Patients on Efavirenz-Based Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Innocent Lule Segamwenge

    2018-01-01

    Full Text Available Objectives. To describe the clinical characteristics of patients presenting with fulminant liver failure after varying periods of exposure to Efavirenz containing antiretroviral medications. Methods. We report a series of 4 patients with human immunodeficiency virus (HIV infection who were admitted with acute liver failure (ALF over a 6-month period. All these patients had been treated with a range of Efavirenz containing antiretroviral regimens and were negative for hepatitis A, B, and C infections as well as other opportunistic infections, all were negative for autoimmune hepatitis, and none had evidence of chronic liver disease or use of alcohol or herbal medications. Information on patient clinical characteristics, current antiretroviral regimen, CD4 count, HIV-1 RNA levels, and clinical chemistry parameters was collected. Informed consent was provided. Results. During a 6-month period, four patients without other known risk factors for acute hepatitis presented with symptomatic drug-induced liver injury with varying symptoms and outcomes. The pattern of liver injury was hepatocellular for all the 4 cases. Liver biopsies were done for all the four cases and the results showed a heavy mixed inflammatory cell infiltrate with eosinophils. For three patients withdrawal of Efavirenz from their antiretroviral regimen was sufficient to restore transaminase levels to normal and led to improvement of clinical symptoms. For one patient his clinical course was characterized by fulminant liver failure and fluctuating episodes of hepatic encephalopathy which ultimately resulted in his death. Conclusion. Hepatotoxicity of Efavirenz is not as rare as previously described in the literature and does actually present with fatal outcomes. The key message to note is that frequent monitoring of liver enzymes should be done at initiation of antiretroviral therapy and should continue throughout the treatment period.

  5. Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

    Directory of Open Access Journals (Sweden)

    Alison E. M. Vickers

    2017-03-01

    Full Text Available Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM, diclofenac (DCF, 1 mM and etomoxir (ETM, 100 μM. Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM and cyclosporin A (CSA, 10 μM, while GSH was affected more than ATP by methimazole (MMI, 500 μM, terbinafine (TBF, 100 μM, and carbamazepine (CBZ 100 μM. Oxidative stress genes were affected by TBF (18%, CBZ, APAP, and ETM (12%–11%, and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%. Apoptosis genes were affected by DCF (14%, while apoptosis plus necrosis were altered by APAP and ETM (15%. Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%, ETM (66%, DCF, TBF, MMI (61%–60%, APAP, CBZ (57%–56%, and DTL (48%. Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%, CBZ and ETM (44%–43%, APAP and DCF (40%–38%, MMI, TBF and CSA (37%–35%. This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

  6. Late Acute Rejection Occuring in Liver Allograft Recipients

    Directory of Open Access Journals (Sweden)

    Eric M Yoshida

    1996-01-01

    Full Text Available To study the effect of immunosuppressive reduction on the incidence and consequence of late acute rejection (LAR in liver allograft recipients, mean daily prednisone dose, mean cyclosporine A (CsA trough and nadir levels were retrospectively reviewed for the nearest 12-week period preceding six episodes of LAR in five liver allograft recipients (group 1. Results were compared with those from a cohort of 12 liver allograft recipients who did not develop LAR (group 2. LAR was defined as acute rejection occurring more than 365 days post-transplantation. Median follow-up for both groups was similar (504 days, range 367 to 1050, versus 511 days, range 365 to 666, not significant. Mean trough CsA levels were lower in patients with LAR compared with those without (224±66 ng/mL versus 233±49 ng/mL but the difference was not statistically significant. In contrast, mean daily prednisone dose (2.5±1.6 mg/ day versus 6.5±2.9 mg/day, P=0.007 and CsA nadir values (129±60 ng/mL versus 186±40 ng/mL, P=0.03 were significantly lower in patients who developed LAR compared with those who did not. Five of six episodes (83% of LAR occurred in patients receiving less than 5 mg/day of prednisone, versus a single LAR episode in only one of 12 patients (8% receiving prednisone 5 mg/day or more (P=0.004. In all but one instance, LAR responded to pulse methylprednisolone without discernible affect on long term graft function. The authors conclude that liver allograft recipients remain vulnerable to acute rejection beyond the first post-transplant year; and reduction of immunosuppressive therapy, particularly prednisone, below a critical, albeit low dose, threshold increases the risk of LAR.

  7. Preliminary investigation of hybrid bioartificial liver support system in treatment of HBV-related acute-on-chronic liver failure

    Directory of Open Access Journals (Sweden)

    YOU Shaoli

    2013-09-01

    Full Text Available ObjectiveTo construct a hybrid bioartificial liver support system and to investigate its safety and efficacy in patients with hepatitis B virus (HBV-related acute-on-chronic liver failure (ACLF. MethodsA hollow fiber bioreactor was constructed using cultured HepG2 cells transfected with human augmenter of liver regeneration gene. Patients with HBV-related ACLF who were hospitalized in our hospital from May 2009 to August 2011 were randomly divided into treatment group (n=10 and control group (n=10. The treatment group was treated using the hybrid bioartificial liver support system, while the control group was treated with conventional plasma exchange. Comparison of means between the two groups was made by independent-samples t test, and comparison of variables before and after treatment was made by paired t test. ResultsOf the 10 patients in treatment group, 7 had improvement in clinical symptoms and were discharged, 1 died of hepatic encephalopathy, 1 died of hepatorenal syndrome, and 1 died of liver failure after discharge. Of the 10 patients in control group, 5 survived, 1 underwent liver transplantation, and 4 died of liver failure. Before treatment, the treatment group and control group had model for end-stage liver disease (MELD scores of 24.26±2.54 and 24.71±2.79, respectively, without significant difference between the two groups (t=1.971, P=0.064. The treatment group had MELD scores of 21.71±2.92, 22.10±4.46, and 19.90±5.43 after 3 days, 1 week, and 4 weeks, respectively, of treatment. At the end of one-year follow-up, the mean serum alpha-fetoprotein levels were 14.24 ng/ml in treatment group and 11.32 ng/ml in control group, and no space-occupying lesions in the liver were found through abdominal ultrasound. ConclusionThe constructed hybrid bioartificial liver support system is effective and safe in the treatment of HBV-related ACLF.

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

    Institute of Scientific and Technical Information of China (English)

    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.

  9. Acute Liver Failure Due to Regorafenib May Be Caused by Impaired Liver Blood Flow: A Case Report.

    Science.gov (United States)

    Akamine, Takaki; Ando, Koji; Oki, Eiji; Saeki, Hiroshi; Nakashima, Yuichiro; Imamura, Y U; Ohgaki, Kippei; Maehara, Yoshihiko

    2015-07-01

    Regorafenib has been approved for treatment of patients with unresectable or recurrent gastrointestinal stromal tumors resistant to imatinib or sunitinib. However, regorafenib has severe side-effects, including acute liver failure. We describe the case of a patient with multiple liver metastases of a small intestinal stromal tumor who experienced acute liver failure while being treated with regorafenib. A 50-year-old patient with an unresectable small intestinal stromal tumor resistant to prior treatment with imatinib and sunitinib was started on regorafenib, but experienced acute liver failure 10 days later. Plasma exchange and steroid pulse treatment improved her liver function. During liver failure, abdominal ultrasonography showed to-and-fro flow in the portal vein. Lactate dehydrogenase concentration was markedly elevated to 1633 U/l. These findings indicate that liver failure in this patient was due to impaired liver blood flow. Regorafenib may impair liver blood flow, inducing acute liver failure. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Current Understanding of Acute Bovine Liver Disease in Australia

    Directory of Open Access Journals (Sweden)

    Elizabeth Read

    2016-12-01

    Full Text Available Acute bovine liver disease (ABLD is a hepatotoxicity principally of cattle which occurs in southern regions of Australia. Severely affected animals undergo rapid clinical progression with mortalities often occurring prior to the recognition of clinical signs. Less severely affected animals develop photosensitization and a proportion can develop liver failure. The characteristic histopathological lesion in acute fatal cases is severe, with acute necrosis of periportal hepatocytes with hemorrhage into the necrotic areas. Currently there are a small number of toxins that are known to cause periportal necrosis in cattle, although none of these have so far been linked to ABLD. Furthermore, ABLD has frequently been associated with the presence of rough dog’s tail grass (Cynosurus echinatus and Drechslera spp. fungi in the pasture system, but it is currently unknown if these are etiological factors. Much of the knowledge about ABLD is contained within case reports, with very little experimental research investigating the specific cause(s. This review provides an overview of the current and most recently published knowledge of ABLD. It also draws on wider research and unpublished reports to suggest possible fungi and mycotoxins that may give rise to ABLD.

  11. Radionuclide imaging of the liver in human fascioliasis

    International Nuclear Information System (INIS)

    Rivera, J.V.; Bermudez, R.H.

    1984-01-01

    The clinical, laboratory, and scintigraphic findings in four cases of human fascioliasis are described. Acute onset of fever, abdominal pain, and weight loss in a person who has ingested watercress constitutes the clinical syndrome often seen. Eosinophilia and alteration in liver function tests, particularly alkaline phosphatase are frequent. Tc-99m sulfur colloid images showed hepatomegaly in four patients, focal defects in two, splenomegaly in three, and increased splenic uptake in two. Gallium citrate (Ga 67) images show increased uptake in the focal lesions in two of two. Sonographic imaging showed focal lucent abnormality in one of three. Liver biopsy findings were nonspecific. The differential diagnosis from other invasive parasitic diseases is discussed. A possible role of hepatic imaging in the evaluation of fascioliasis is suggested

  12. A Pilot Study of Mesenchymal Stem Cell Therapy for Acute Liver Allograft Rejection

    OpenAIRE

    Shi, Ming; Liu, Zhenwen; Wang, Ying; Xu, Rounan; Sun, Yanling; Zhang, Min; Yu, Xi; Wang, Hongbo; Meng, Lingzhan; Su, Haibin; Jin, Lei; Wang, Fu‐Sheng

    2017-01-01

    Abstract Acute allograft rejection remains common after liver transplantation despite modern immunosuppressive agents. In addition, the long‐term side effects of these regimens, including opportunistic infections, are challenging. This study evaluated the safety and clinical feasibility of umbilical cord‐derived mesenchymal stem cell (UC‐MSC) therapy in liver transplant patients with acute graft rejection. Twenty‐seven liver allograft recipients with acute rejection were randomly assigned int...

  13. Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen

    Directory of Open Access Journals (Sweden)

    Tomáš Zárybnický

    2018-06-01

    Full Text Available Monoterpenes R-pulegone (PUL and R-menthofuran (MF, abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound on cell viability and microRNA (miRNA expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue, while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people.

  14. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure

    DEFF Research Database (Denmark)

    Wendon,, Julia; Cordoba, Juan; Dhawan, Anil

    2017-01-01

    abnormality of liver blood tests in an individual without underlying chronic liver disease. The disease process is associated with development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. Several important measures are immediately...... necessary when the patient presents for medical attention. These, as well as additional clinical procedures will be the subject of these clinical practice guidelines.......The term acute liver failure (ALF) is frequently applied as a generic expression to describe patients presenting with or developing an acute episode of liver dysfunction. In the context of hepatological practice, however, ALF refers to a highly specific and rare syndrome, characterised by an acute...

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  16. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice

    International Nuclear Information System (INIS)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl 3 ) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified.

  17. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice.

    Science.gov (United States)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-11

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl₃) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Dataset of protein species from human liver

    Directory of Open Access Journals (Sweden)

    Stanislav Naryzhny

    2017-06-01

    Full Text Available This article contains data related to the research article entitled “Zipf׳s law in proteomics” (Naryzhny et al., 2017 [1]. The protein composition in the human liver or hepatocarcinoma (HepG2 cells extracts was estimated using a filter-aided sample preparation (FASP protocol. The protein species/proteoform composition in the human liver was determined by two-dimensional electrophoresis (2-DE followed by Electrospray Ionization Liquid Chromatography-Tandem Mass Spectrometry (ESI LC-MS/MS. In the case of two-dimensional electrophoresis (2-DE, the gel was stained with Coomassie Brilliant Blue R350, and image analysis was performed with ImageMaster 2D Platinum software (GE Healthcare. The 96 sections in the 2D gel were selected and cut for subsequent ESI LC-MS/MS and protein identification. If the same protein was detected in different sections, it was considered to exist as different protein species/proteoforms. A list of human liver proteoforms detected in this way is presented.

  19. Acute Fatty Liver of Pregnancy: A Clinical-Paraclinical Survey

    Directory of Open Access Journals (Sweden)

    Mohammad Jafari

    2015-02-01

    Full Text Available Background Acute Fatty Liver of Pregnancy (AFLP is one of the serious complications of the pregnancy period. Surveying the laboratory and clinical signs is effective in timely prognosis and fast treatment of this illness. Objectives The current study aimed to evaluate AFLP among the hospitalized subjects. Patients and Methods This retrospective study was conducted on clinical and preclinical records of 25 females with AFLP for maternal and perinatal prognosis from 2000 to 2009. The data was analyzed using SPSS ver. 19. Results The patients aged 16 - 45 years old with one to four pregnancies (pregnancy; they were 24 to 39 weeks pregnant with the mean of 33.56 weeks, and 56% were multifarious. The most prevalent clinical symptoms were nausea, vomiting, abdominal pain, headache, pruritus, and icterus. The laboratory signs included disorders of liver, coagulation, kidney, and hypoglycemia. Nausea and vomiting in the first and second age groups (Group 1, patients were 35 years. were the most prevalent symptoms. No patient had fever, ascites, and polydipsia. There was one case of mother and fetal death. Conclusions In the current study, the clinical and paraclinical signs of AFLP were mostly - liver, coagulation, kidney, and hypoglycemia disorders. Considering that patients mostly refer in three phases of clinical, laboratory, and complications, it is essential to evaluate the suspected ones who present clinical symptoms especially nausea, vomiting and abdominal pain.

  20. Acute kidney injury in liver transplant candidates : A position paper on behalf of the Liver Intensive Care Group of Europe

    NARCIS (Netherlands)

    Angeli, Paolo; Bezinover, Dimitri; Biancofiore, Gianni; Bienholz, Anja; Findlay, James; Paugam Burtz, Catherine; Reyntjens, Koen; Sakai, Tetsuro; Saner, Fuat H; Tomescu, Dana; Wagener, Gebhard; Weiss, Emmanuel

    INTRODUCTION: Acute kidney injury is associated with high mortality in the perioperative period of liver transplantation. The aim of this position paper was to provide an up-to-date overview with special emphases on diagnosis, risk factors, and treatment. EVIDENCE ACQUISITION: The Liver Intensive

  1. Early plasmapheresis and rituximab for acute humoral rejection after ABO-compatible liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Nassim Kamar; Laurence Lavayssière; Fabrice Muscari; Janick Selves; Céline Guilbeau-Frugier; Isabelle Cardeau; Laure Esposito; Olivier Cointault; Marie Béatrice Nogier; Jean Marie Peron; Philippe Otal; Marylise Fort; Lionel Rostaing

    2009-01-01

    Acute humoral rejection (AHR) is uncommon after ABOcompatible liver transplantation. Herein, we report two cases of AHR treated with plasmapheresis and rituximab in two ABO-compatible liver-transplant patients with preformed anti-human leukocyte antigen donor-specific antibodies. Patient 1 experienced a biopsy-proven AHR at day 10 post-transplant. She was treated by steroid pulses, and OKT3. Because of persisting signs of biopsy-proven AHR at day 26, she was treated by plasmapheresis and rituximab. Liver enzyme levels did not improve, and she died on day 41. Patient 2 experienced a biopsy-proven AHR on day 10 post-transplant. She was treated by steroid pulses, plasmapheresis, and rituximab.Liver enzymes returned to within normal range 18 dafter diagnosis. Liver biopsies, at 3 and 9 mo post-transplant,showed complete resolution of AHR. We conclude that plasmapheresis should be started as soon as AHR is diagnosed, and be associated with a B-cell depleting agent. Rituximab may be considered as a first-line therapy.

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

    Science.gov (United States)

    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.

  3. Molecular Structure of Human-Liver Glycogen.

    Directory of Open Access Journals (Sweden)

    Bin Deng

    Full Text Available Glycogen is a highly branched glucose polymer which is involved in maintaining blood-sugar homeostasis. Liver glycogen contains large composite α particles made up of linked β particles. Previous studies have shown that the binding which links β particles into α particles is impaired in diabetic mice. The present study reports the first molecular structural characterization of human-liver glycogen from non-diabetic patients, using transmission electron microscopy for morphology and size-exclusion chromatography for the molecular size distribution; the latter is also studied as a function of time during acid hydrolysis in vitro, which is sensitive to certain structural features, particularly glycosidic vs. proteinaceous linkages. The results are compared with those seen in mice and pigs. The molecular structural change during acid hydrolysis is similar in each case, and indicates that the linkage of β into α particles is not glycosidic. This result, and the similar morphology in each case, together imply that human liver glycogen has similar molecular structure to those of mice and pigs. This knowledge will be useful for future diabetes drug targets.

  4. Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Nobuhiro Nakamoto

    2017-10-01

    Full Text Available Summary: Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-β through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance. : Nakamoto et.al. find that Lactobacillus accumulates in the gut and activates IL-22 production by innate lymphoid cells during acute liver injury. Gut-derived IL-22 contributes to liver tolerance via induction of regulatory DCs. Keywords: immune tolerance, dendritic cell, innate lymphoid cell, acute liver injury, interleukin-10, interleukin-22, microbiota, dysbiosis

  5. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis

    DEFF Research Database (Denmark)

    Markwardt, Daniel; Holdt, Lesca; Steib, Christian

    2017-01-01

    The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (Cys...

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

    DEFF Research Database (Denmark)

    Bernal, William; Murphy, Nicholas; Brown, Sarah

    2016-01-01

    BACKGROUND & AIMS: Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown...... by sealed envelope to targeted temperature management (TTM) groups of 34°C (MH) or 36°C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse...

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

    DEFF Research Database (Denmark)

    Almdal, T; Schroeder, T; Ranek, L

    1989-01-01

    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 range...

  8. HUMAN LIVER SLICES EXPRESS THE SAME LIDOCAINE BIOTRANSFORMATION RATE AS ISOLATED HUMAN HEPATOCYTES

    NARCIS (Netherlands)

    OLINGA, P; MEIJER, DKF; SLOOFF, MJH; GROOTHUIS, GMM; Merema, M.T.

    1993-01-01

    In order to investigate whether liver slices are a valuable tool for the assessment of drug metabolism in human liver, we compared the phase I metabolism of lidocaine in human liver slices and hepatocytes prepared from three human livers. Lidocaine is mainly metabolised to monoethylglycinexylidide

  9. [Effect of acute biliary pancreatitis on liver metabolism of phenazone].

    Science.gov (United States)

    Hartleb, M; Nowak, A; Nowakowska-Duława, E; Mańczyk, I; Becker, A; Kacperek, T

    1990-03-01

    In 22 patients with acute pancreatitis caused by biliary calculi and 9 healthy controls the rate of hepatic elimination of phenazone was measured. The aim of the study was evaluation of the oxidative-detoxicating action of the liver in this disease in relation to its severity. In pancreatitis patients the half-time (T2) of phenazone was significantly (p less than 0.01 longer than in healthy subjects (23.6 +/- 10.5 vs 13.2 +/- 7.2 hrs). The T2 of phenazone was not correlated with the concentrations of transaminases, bilirubin and prothrombin, but was correlated positively with the concentration of hepatic lactic dehydrogenase (p less than 0.001). In the initial stage of pancreatitis the T2 of phenazone was without prognostic significance and showed no agreement with Ranson's clinical-laboratory classification of the severity of the disease. The degree of impairment of the hepatic metabolism of phenazone measured with the percent difference between T2 of phenazone in both tests was significantly (p less than 0.05) greater in the group of patients with complications than in those without pancreatitis complications (70.7 +/- 64.4% vs 21.4 +/- 16.2%). Biliary pancreatitis impairs the oxidative-reductive function of the liver proportionally to the degree of hepatic lactic dehydrogenase in the serum. Evaluation of the rate of hepatic elimination of phenazone in the initial stage of this pancreatitis was without prognostic importance for the severity of the disease.

  10. Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Takanori Takebe

    2017-12-01

    Full Text Available Summary: Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC. By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108. Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations. : With the goal of clinical translation of liver bud transplant therapy, Takebe et al. established a massive organoid production platform from endoderm, endothelial, and mesenchymal progenitor populations specified entirely from human iPSCs, reproducibly demonstrating functionality both in vitro and in vivo. Keywords: iPSC, liver bud, organoid, transplantation, self-organization, endothelial, mesenchymal, liver failure, clinical grade

  11. Pyruvate dehydrogenase complex and lactate dehydrogenase as targets for therapy of acute liver failure.

    Science.gov (United States)

    Ferriero, Rosa; Nusco, Edoardo; De Cegli, Rossella; Carissimo, Annamaria; Manco, Giuseppe; Brunetti-Pierri, Nicola

    2018-03-23

    Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate in the nucleus to regulate histone acetylation and gene expression. Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-Ab, α-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by Gene Ontology Enrichment Analysis. Efficacy of histone acetyltransferase inhibitor garcinol and LDH inhibitor galloflavin at reducing liver damage was evaluated in mice with induced hepatotoxicity. Levels and activities of PDHC and LDH were increased in cytoplasmatic and nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-coA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to response to damage. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival. PDHC and LDH translocate to the nucleus and are targets for therapy of acute liver failure. Acute liver failure is a rapidly progressive and life-threatening deterioration of liver function resulting in high mortality and

  12. Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Tak, Eunyoung [Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Dong-Hwan; Kim, Seok-Hwan; Park, Gil-Chun [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jun, Dae Young; Lee, Jooyoung [Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Bo-hyun [Department of Surgery, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of); Kirchner, Varvara A. [Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN (United States); Hwang, Shin [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Song, Gi-Won, E-mail: drsong71@amc.seoul.kr [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Lee, Sung-Gyu [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2017-01-01

    Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5′-nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care. - Highlights: • HIF-1a is stabilized during acute liver failure • Upregulation of CD39 and CD73 following acute liver failure • CD39 and CD73 are transcriptionally induced by HIF-1a • Deletion of Cd39 and CD73 aggravates murine acute liver failure • DMOG treatment induces HIF-1a stabilization, CD39 and CD73 during acute liver failure in WT mice.

  13. Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Mei Liu

    2014-01-01

    Full Text Available Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by D-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.

  14. Radiological evaluation of a liver simulator in comparison to a human real liver

    International Nuclear Information System (INIS)

    Toledo, Janine M.; Campos, Tarcisio P.R. de

    2009-01-01

    The present study evaluates the radiological features of a human real healthy liver reproducing its characteristics on a developed liver simulator. The radiological evaluation will be performed through radiological methods such as CT and X-ray images, density and weight measurements, as well as representation of the coloration and texture. According to literature, the liver is the highest weight organ and gland of the body, weighing approximately 1,5 kg. On the liver, the nutrients are absorbed from the digestive tract and are prosecuted and stored for future use by other organs. Also the liver is responsible for the neutralization and elimination of various toxic substances. Thus, it is an interface between the digestive system and the blood. Besides, this organ is the principal source of plasmatic proteins like the albumin, transport of graxos oily acids. Due to its proprieties, the liver holds a large amount of radionuclides on any uptake from external source. The liver simulator was designed to have the same density, weight and corresponding shape. The radiographic image was produced by conventional X-rays machine, in which the radiographic applied parameters were the same applied to abdomen. The result of the radiographic and CT images demonstrates radiological equivalence between the simulator and human real liver. Hounsfield number of the synthetic liver tissue was found on the range of human livers. Therefore, due to its similar shape, chemical composition, radiological response, the liver simulator can be used to investigate ionizing radiation procedures during radiation therapy intervention. (author)

  15. Acute fatty liver of pregnancy. CT scan imaging in 4 cases

    International Nuclear Information System (INIS)

    Coche, G.; Moran, V.; Schmitt, M.; Boillot, A.; Miguet, J.P.; Hadni-Bresson, S.; Weill, F.S.

    1987-01-01

    Acute fatty liver of pregnancy is a disease of the third trimester, generally considered to be rare and to have a grave prognosis. Histologically the characteristic fine droplet steatosis usually produces distinct vacuolization. Successful treatment depends on accurate diagnosis and early delivery. Computed tomography is of value in the diagnosis of fatty liver through liver and spleen attenuation value measurements. We reviewed 4 cases of acute fatty liver of pregnancy. Computed tomography was performed in two cases and was very helpful in the diagnosis of this condition [fr

  16. Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

    Directory of Open Access Journals (Sweden)

    Andrea Baiocchini

    Full Text Available Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis. Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.

  17. Brain Aquaporin-4 in Experimental Acute Liver Failure

    Science.gov (United States)

    Rama Rao, Kakulavarapu V.; Jayakumar, Arumugam R.; Tong, Xiaoying; Curtis, Kevin M.; Norenberg, Michael D.

    2016-01-01

    Intracranial hypertension due to brain edema and associated astrocyte swelling is a potentially lethal complication of acute liver failure (ALF). Mechanisms of edema formation are not well understood but elevated levels of blood and brain ammonia and its byproduct glutamine have been implicated in this process. We examined mRNA and protein expression of the water channel protein aquaporin-4 (AQP4) in cerebral cortex in a rat model of ALF induced by the hepatotoxin thioacetamide. Rats with ALF showed increased AQP4 protein in the plasma membrane (PM). Total tissue levels of AQP4 protein and mRNA levels were not altered indicating that increased AQP4 is not transcriptionally mediated but is likely due to a conformational change in the protein, i.e. a more stable anchoring of AQP4 to the PM and/or interference with its degradation. By immunohistochemistry there was an increase in AQP4 immunoreactivity in the PM of perivascular astrocytes in ALF. Rats with ALF showed increased levels of α-syntrophin, a protein involved in the anchoring of AQP4 to perivascular astrocytic end-feet. Increased AQP4 and α-syntrophin levels were inhibited by L-histidine, an inhibitor of glutamine transport into mitochondria, suggesting a role for glutamine in the increase of PM levels of AQP4. These results indicate that increased AQP4 PM levels in perivascular astrocytic end-feet are likely critical to the development of brain edema in ALF. PMID:20720509

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

    International Nuclear Information System (INIS)

    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. (author)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  20. Diagnostic value of liver scintigraphy in fulminant hepatitis and severe acute hepatitis

    International Nuclear Information System (INIS)

    Shiomi, Susumu; Ikeoka, Naoko; Minowa, Takami; Kuroki, Tetsuo; Harihara, Shigeyoshi; Yamamoto, Sukeo; Ochi, Hironobu; Monna, Takeyuki

    1985-01-01

    Liver scintigraphy was performed in 12 cases with fulminant hepatitis, in 8 cases with severe acute hepatitis and in 44 cases with acute hepatitis. Scintiphotoes of severe hepatitis showed reduction of liver size, marked visualization of the bone marrow and the spleen, so this pattern was useful to differentiate from acute hepatitis. Relative size of the liver calculated by A.L.I. (anterior liver index) showed significant reduction in severe hepatitis compared with that of acute hepatitis. Three of five patients with died of severe hepatitis showed high uptake in the lung and ribs, but none of fifteen patients with severe hepatitis who recovered showed the abnormal accumulation in the lung and in the ribs. (author)

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

    DEFF Research Database (Denmark)

    Bjerring, P N; Larsen, F S

    2013-01-01

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

  2. Acute Liver Allograft Antibody-Mediated Rejection: an inter-institutional study of routine histopathological features

    OpenAIRE

    O'Leary, Jacqueline G.; Shiller, S. Michelle; Bellamy, Christopher; Nalesnik, Michael A.; Kaneku, Hugo; Terasaki, Paul I.; Klintmalm, Göran B.; Demetris, Anthony J.

    2014-01-01

    Acute antibody-mediated rejection (AMR) occurs in a minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, a generalizable scoring system used to trigger a more in-depth analysis is needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases that were evaluated blindly by 4 independent transplant...

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

    Science.gov (United States)

    Bispo, Miguel; Valente, Ana; Maldonado, Rosário; Palma, Rui; Glória, Helena; Nóbrega, João; Alexandrino, Paula

    2009-06-21

    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.

  4. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    International Nuclear Information System (INIS)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

    2016-01-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

  5. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    Energy Technology Data Exchange (ETDEWEB)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States); Uehara, Takeki; Kato, Yuki [Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka (Japan); Kono, Hiroshi [First Department of Surgery, University of Yamanashi, Yamanashi (Japan); Bataller, Ramon [Division of Gastroenterology & Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, NC (United States); Rusyn, Ivan, E-mail: irusyn@tamu.edu [Department of Veterinary Integrative Biosciences, Texas A& M University, College Station, TX (United States)

    2016-11-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl{sub 4})-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl{sub 4} (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl{sub 4}. We observed that combined treatment with CCl{sub 4} and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis.

  6. Extracorporeal perfusion for the treatment of acute liver failure

    NARCIS (Netherlands)

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

    2000-01-01

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

  7. Detection of human leukocyte antigen compatibility and antibodies in liver transplantation in China

    Institute of Scientific and Technical Information of China (English)

    Xue-Qin Meng; Xuan Zhang; Jun Fan; Lin Zhou; Bing Hao; Xiao-Ming Chen; Wei-Hang Ma; Shu-Sen Zheng

    2009-01-01

    BACKGROUND: The exact roles of human leukocyte antigen (HLA) compatibility, HLA antibodies and underlying diseases in acute rejection of liver transplants are not clear. Moreover, cytomegalovirus (CMV) infection, one of the most common infections after transplantation, is related to HLA genotype and the incidence of acute rejection. METHODS: Since there are controversial reports, we analyzed the impact of HLA matching, HLA antibodies and underlying diseases in 38 liver transplant recipients in China, and assessed the association of CMV infection and HLA compatibility. RESULTS: The frequency of no HLA compatibility was high in patients without antigenemia (P=0.019). All 17 patients with HLA-A matching developed antigenemia (P0.05). In patients with acute rejection, no differences were found in the incidence of acute rejection in transplants for hepatitis B, tumors, or combined hepatitis B and tumors (P>0.05).CONCLUSIONS: There are fewer acute rejections in transplants with more HLA compatibilities. Speciifc investigations of underlying diseases and HLA typing may be necessary in liver transplantation. The mechanisms of CMV infection and HLA matching should be further studied. HLA before transplantation should be examined for the prevention of acute rejection and CMV infection.

  8. ACTION OF VITAMIN E ON EXPERIMENTAL SEVERE ACUTE LIVER FAILURE.

    Science.gov (United States)

    Miguel, Fabiano Moraes; Schemitt, Elizângela Gonçalves; Colares, Josieli Raskopf; Hartmann, Renata Minuzzo; Morgan-Martins, Maria Isabel; Marroni, Norma Possa

    2017-01-01

    Severe Acute Liver Failure (ALF) is a life-threatening clinical syndrome characterized by hepatocyte necrosis, loss of hepatic architecture, and impairment of liver functions. One of the main causes of ALF is hepatotoxicity from chemical agents, which damage hepatocytes and result in increase of reactive oxygen species. The vitamin E isoform is the one with the strongest biological antioxidant activity. To evaluate the antioxidant effect of vitamin E in this ALF model. We used 56 rats (mean weight of 300 g) divided into eight groups, four groups assessed at 24 hours and 4 assessed at 48 hours after induction: control group (CO); Vitamin E (Vit. E); Thioacetamide (TAA) and Thioacetamide + Vitamina E (TAA+Vit.E). Rats were submitted to injections of thioacetamide (400 mg/kg i.p.) at baseline and 8 hours later. Vitamin E (100 mg/kg ip) was administered 30 minutes after the second dose of thioacetamide. The 48-hour group rats received two additional doses of vitamin E (24h and 36h). At 24h or 48 hours after the administration of the first dose of TAA, rats were weighed and anesthetized and their blood sampled for evaluation of liver integrity through enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Liver tissue was sampled for assessment of lipid peroxidation (LPO) by the technique TBARS, antioxidant enzymes SOD, CAT, GPx and GST activity, levels of the NO 2 /NO 3 and histology by H&E in two times. The results were expressed as mean ± standard deviation and statistically analyzed by ANOVA followed by Student-Newman-Keuls, with P E, we observed a reduction in liver enzymes AST (U/L) (101.32±19.45 in 24 hours and 97.85±29.65 in 48 hours) related to the TAA group (469.56± 0.69 in 24 hours and 598.23±55.45 in 48 hours) and ALT (U/L) (76.59±8.56 in 24 hours and 68.47±6.49 in 48 hours) compared to the TAA group (312.21±10.23 in 24 hours and 359.15±17.58 in 48 hours). There was a reduction of LPO (nmol/mg Prot) in the TAA+Vit.E group (0

  9. Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience.

    Directory of Open Access Journals (Sweden)

    Ricky H Bhogal

    2011-03-01

    Full Text Available Successful and consistent isolation of primary human hepatocytes remains a challenge for both cell-based therapeutics/transplantation and laboratory research. Several centres around the world have extensive experience in the isolation of human hepatocytes from non-diseased livers obtained from donor liver surplus to surgical requirement or at hepatic resection for tumours. These livers are an important but limited source of cells for therapy or research. The capacity to isolate cells from diseased liver tissue removed at transplantation would substantially increase availability of cells for research. However no studies comparing the outcome of human hepatocytes isolation from diseased and non-diseased livers presently exist. Here we report our experience isolating human hepatocytes from organ donors, non-diseased resected liver and cirrhotic tissue. We report the cell yields and functional qualities of cells isolated from the different types of liver and demonstrate that a single rigorous protocol allows the routine harvest of good quality primary hepatocytes from the most commonly accessible human liver tissue samples.

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Oriel Nissim

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

  13. Japanese-style intensive medical care improves prognosis for acute liver failure and the perioperative management of liver transplantation.

    Science.gov (United States)

    Inoue, K; Watanabe, T; Maruoka, N; Kuroki, Y; Takahashi, H; Yoshiba, M

    2010-12-01

    The Japanese style of intensive medical care for acute liver failure has yielded high survival rates. The care system comprises artificial liver support (ALS) together with treatment for the underlying disease. Plasma exchange in combination with high-volume hemodiafiltration using an high performance membrane has become the standard ALS system. It is safe, efficiently removing more low and middle molecular weight toxic substances than other methods because of the large volumes of buffer (more than 200 L per session), resulting in recovery from coma in patients with severe fulminant hepatitis, a status comparable with the ahepatic state. This ALS is therefore an effective tool to sustain patients with fulminant hepatitis in a favorable condition until liver function recovers or liver transplantation becomes available. The accompanying treatment for underlying disease serves to limit the liver destruction that hampers regeneration. The treatment has remarkably improved the prognosis for patients with subacute types of fulminant hepatitis, which generally carry a less favorable prognosis than the acute type. This treatment system thus provides more time for physicians to assess the indications for liver transplantation as well as giving the patient a greater chance of undergoing transplantation. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    International Nuclear Information System (INIS)

    Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  15. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  16. Parvovirus B19 Infection in a Fatal Case of Acute Liver Failure.

    Science.gov (United States)

    Leon, Luciane Almeida Amado; Alves, Arthur Daniel Rocha; Garcia, Rita de Cássia Nasser Cubel; Melgaço, Juliana Gil; de Paula, Vanessa Salete; Pinto, Marcelo Alves

    2017-12-01

    B19V has been proposed as an etiologic agent for hepatitis, mainly in children, but this is a rare clinical occurrence. In this article, we report a case of non-A-E acute liver failure in an immunocompetent child with B19 infection. The clinical findings of severe anemia and pancytopenia combined with the detection of anti-B19 Immunoglobulin G (IgG), B19 DNA and B19 mRNA in liver indicate a persistent infection and suggest a diagnosis of parvovirus B19-associated acute liver failure.

  17. Interaction of rocuronium with human liver cytochromes P450

    OpenAIRE

    Anzenbacherova, Eva; Spicakova, Alena; Jourova, Lenka; Ulrichova, Jitka; Adamus, Milan; Bachleda, Petr; Anzenbacher, Pavel

    2015-01-01

    Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver micro...

  18. Acute-on-chronic liver failure: causes, clinical characteristics and predictors of mortality

    International Nuclear Information System (INIS)

    Ali, A.; Luck, N.H.

    2017-01-01

    Objective: To determine the causes, characteristics and predictors of mortality in patients with acute-on-chronic liver failure (ACLF). Study Design: Cross-sectional study. Place and Duration of Study:Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, from July 2014 to June 2016. Methodology:All patients with acute-on-chronic liver disease (ACLD) with ages > 12 were included. Patients with ACLF, as defined by the Asian Pacific Association for the Study of Liver (APASL, 2014) were identified. Predictors of mortality were identified using chi-square or Fisher's exact test. Results: Included in the study were 72 patients with mean age of 36.71 years, 46 (63.9%) being males. Among them, 61 developed ACLF. Commonest causes of chronic liver disease (CLD) were chronic viral hepatitis (37, 51.4%) and autoimmune hepatitis (14, 19.4%). Commonest causes of acute liver injury (ALI) were acute viral hepatitis (24, 33.3%) and drug induced liver injury (DILI) (17, 23.6%). Among those with ACLF, 24 (39.3%) patients died with median survival of 17.1 +-13.5 days. Mortality was significantly associated with Child Turcotte Pugh (CTP) score =>13 (p=0.010), model for end-stage liver disease (MELD) score =>30 (p=0.001), age >40 years (p=0.036), organ failures (OF) =>3 (p 3, CTP =>13, MELD =>30, age >40 years, PSE, renal failure and urosepsis. (author)

  19. Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology.

    Directory of Open Access Journals (Sweden)

    Matthew J Robertson

    Full Text Available Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.

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

    DEFF Research Database (Denmark)

    Bernal, William; Wang, Yanzhong; Maggs, James

    2016-01-01

    : The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation......BACKGROUND: Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver...... transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death. METHODS: Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK...

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

    Directory of Open Access Journals (Sweden)

    Honglei eWeng

    2015-06-01

    Full Text Available 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  3. Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

    Science.gov (United States)

    Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

    1989-01-01

    A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

  4. Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

    Science.gov (United States)

    Kok, Beverley; Lester, Erica L W; Lee, William M; Hanje, A James; Stravitz, R Todd; Girgis, Safwat; Patel, Vaishali; Peck, Joshua R; Esber, Christopher; Karvellas, Constantine J

    2018-03-21

    Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Assessment of emerging biomarkers of liver injury in human subjects.

    Science.gov (United States)

    Schomaker, Shelli; Warner, Roscoe; Bock, Jeff; Johnson, Kent; Potter, David; Van Winkle, Joyce; Aubrecht, Jiri

    2013-04-01

    Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug-induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury.

  7. Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise.

    Science.gov (United States)

    Pillon Barcelos, Rômulo; Freire Royes, Luiz Fernando; Gonzalez-Gallego, Javier; Bresciani, Guilherme

    2017-02-01

    The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.

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

    Science.gov (United States)

    Araujo, James L; Worman, Howard J

    2015-05-06

    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. 2015 BMJ Publishing Group Ltd.

  9. Effect of acute beer ingestion on the liver: studies in female mice.

    Science.gov (United States)

    Kanuri, Giridhar; Wagnerberger, Sabine; Landmann, Marianne; Prigl, Eva; Hellerbrand, Claus; Bischoff, Stephan C; Bergheim, Ina

    2015-04-01

    The aim of the present study was to assess whether the effects of acute consumption of stout or pilsner beer on the liver differ from those of plain ethanol in a mouse model. Seven-week-old female C57BL/6J mice received either ethanol, stout or pilsner beer (ethanol content: 6 g/kg body weight) or isocaloric maltodextrin solution. Plasma alanine transaminase, markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade as well as lipid peroxidation and fibrogenesis in the liver were measured 12 h after acute ethanol or beer intake. Acute alcohol ingestion caused a marked ~11-fold increase in hepatic triglyceride accumulation in comparison to controls, whereas in mice exposed to stout and pilsner beer, hepatic triglyceride levels were increased only by ~6.5- and ~4-fold, respectively. mRNA expression of sterol regulatory element-binding protein 1c and fatty acid synthase in the liver did not differ between alcohol and beer groups. In contrast, expression of myeloid differentiation primary response gene 88, inducible nitric oxide synthases, but also the concentrations of 4-hydroxynonenal protein adducts, nuclear factor κB and plasminogen activator inhibitor-1 were induced in livers of ethanol treated mice but not in those exposed to the two beers. Taken together, our results suggest that acute ingestion of beer and herein especially of pilsner beer is less harmful to the liver than the ingestion of plain ethanol.

  10. Dengue hemorrhagic fever complicated with acute liver failure: a case report.

    Science.gov (United States)

    Dalugama, Chamara; Gawarammana, Indika Bandara

    2017-12-08

    Dengue is a common arboviral infection with a clinically diverse spectrum of presentations. Although hepatic dysfunction is commonly identified in patients will dengue illness, acute liver failure is rare. The etiopathogenesis of hepatic dysfunction is multifactorial and related to direct viral invasion of hepatocytes, immunological factors and hypoxia particularly in cases of shock in dengue hemorrhagic fever. Ideal management of dengue-related hepatic dysfunction and acute liver failure is still debated. We report a 53-year-old Sri Lankan Sinhalese male with serologically confirmed dengue fever presenting with evidence of plasma leakage developing acute liver failure evidenced by deranged liver functions, coagulopathy and altered sensorium. In addition to the 'standard care', the patient was managed with intravenous N-acetyl cysteine and blood transfusions even in the absence of bleeding or dropping packed cell volume (PCV), targeting a higher PCV in anticipation of better oxygenation at tissue level. He made a full recovery with no sequential infections. N-acetyl cysteine and packed cell transfusion aiming at a higher PCV to maintain adequate tissue perfusion during shock may be beneficial in acute liver failure due to dengue virus. Large randomized trials should be carried out to establish the efficacy of these treatment strategies to support these observations and change the current practice.

  11. DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

    Science.gov (United States)

    Chen, Hanqing; Shen, Feng; Sherban, Alex; Nocon, Allison; Li, Yu; Wang, Hua; Xu, Ming-Jiang; Rui, Xianliang; Han, Jinyan; Jiang, Bingbing; Lee, Donghwan; Li, Na; Keyhani-Nejad, Farnaz; Fan, Jian-Gao; Liu, Feng; Kamat, Amrita; Musi, Nicolas; Guarente, Leonard; Pacher, Pal; Gao, Bin; Zang, Mengwei

    2018-02-19

    Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. The dysregulation of SIRT1

  12. Scrub typhus causing neonatal hepatitis with acute liver failure-A case series.

    Science.gov (United States)

    Vajpayee, Shailja; Gupta, R K; Gupta, M L

    2017-05-01

    Neonatal hepatitis with acute liver failure due to varied etiology including various infections is reported in the past. Scrub typhus as a cause of neonatal hepatitis has rarely been reported in literature. A high index of clinical suspicion is required for early diagnosis and timely treatment. Severity and prognosis of the disease varies widely because several different strains of Orientia tsutsugamushi exist with different virulence. Delayed diagnosis can result in complication and significant morbidity and mortality. Here, we report three cases of neonatal hepatitis with acute liver failure caused by scrub typhus to increase awareness.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF.......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....

  14. Toxicoproteomic assessment of liver responses to acute pyrrolizidine alkaloid intoxication in rats.

    Science.gov (United States)

    Li, Yan-Hong; Tai, William Chi-Shing; Khan, Imran; Lu, Cheng; Lu, Yao; Wong, Wing-Yan; Chan, Wood-Yee; Wendy Hsiao, Wen-Luan; Lin, Ge

    2018-04-03

    A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  16. Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days

    NARCIS (Netherlands)

    Starokozhko, Viktoriia; Vatakuti, Suresh; Schievink, Bauke; Merema, Marjolijn T.; Asplund, Annika; Synnergren, Jane; Aspegren, Anders; Groothuis, Geny M. M.

    Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and

  17. Parvovirus B19 in an Immunocompetent Adult Patient with Acute Liver Failure: An Underdiagnosed Cause of Acute Non-A-E Viral Hepatitis

    Directory of Open Access Journals (Sweden)

    J Kee Ho

    2005-01-01

    Full Text Available There are occasional pediatric reports of parvovirus B19-associated transient acute hepatitis and hepatic failure. A case of a 34-year-old immunocompetent woman who developed severe and prolonged but self-limited acute hepatitis and myelosuppression following acute parvovirus B19 infection is reported. Parvovirus B19 may be the causative agent in some adult cases of acute non-A-E viral hepatitis and acute liver failure.

  18. A Systematic Review on Prognostic Indicators of Acute Liver Failure and Their Predictive Value for Poor Outcome

    NARCIS (Netherlands)

    Wlodzimirow, Kama A.; Eslami, Saeid; Abu-Hanna, Ameen; Nieuwoudt, Martin; Chamuleau, Robert A. F. M.

    2014-01-01

    This review provides a large amount of information, including the extensive list of worldwide used indicators to predict outcome in patients with acute liver failure. There is large heterogeneity in prognostic indicators of acute liver failure, methods of measurement, complexity of calculation and

  19. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen

    International Nuclear Information System (INIS)

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA −/− ). We found that MsrA −/− mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA +/+ ). The central lobule area of the MsrA −/− liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA −/− than in MsrA +/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA −/− than in MsrA +/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA −/− than in MsrA +/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. - Highlights: • MsrA deficiency increases APAP-induced liver damage. • MsrA deletion enhances APAP-induced hepatic GSH depletion and oxidative stress. • MsrA deficiency induces more profound activation of Nrf2 in response to APAP. • MsrA protects the liver from APAP-induced toxicity.

  20. A study of human liver ferritin and chicken liver and spleen using Moessbauer spectroscopy with high velocity resolution

    Energy Technology Data Exchange (ETDEWEB)

    Oshtrakh, M. I., E-mail: oshtrakh@mail.utnet.ru [Ural State Technical University-UPI, Faculty of Physical Techniques and Devices for Quality Control (Russian Federation); Milder, O. B.; Semionkin, V. A. [Ural State Technical University-UPI, Faculty of Experimental Physics (Russian Federation)

    2008-01-15

    Lyophilized samples of human liver ferritin and chicken liver and spleen were measured at room temperature using Moessbauer spectroscopy with high velocity resolution. An increase in the velocity resolution of Moessbauer spectroscopy permitted us to increase accuracy and decrease experimental error in determining the hyperfine parameters of human liver ferritin and chicken liver and spleen. Moessbauer spectroscopy with high velocity resolution may be very useful for revealing small differences in hyperfine parameters during biomedical research.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury

    Directory of Open Access Journals (Sweden)

    Henning W Zimmermann

    2012-10-01

    Full Text Available Different etiologies such as drug toxicity, acute viral hepatitis B or acetaminophen poisoning can cause acute liver injury (ALI or even acute liver failure (ALF. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF, interleukin-6 (IL-6, IL-1-beta or monocyte chemoattractant protein 1 (MCP-1, CCL2 as well as activating other non-parenchymal liver cells, e.g. endothelial or hepatic stellate cells (HSC. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g. via caspase activation, but also activate protective signaling pathways, e.g. via nuclear factor kappa B (NF-kB. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+ monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1 are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.

  3. A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Lay Teng Ang

    2018-02-01

    Full Text Available How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs. Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah−/−Rag2−/−Il2rg−/− mouse model of liver failure.

  4. Acute fish liver intoxication induced blisters formation and generalized skin peeling.

    Science.gov (United States)

    Chang, Chih-Hao; Lu, Chun-Wei; Chung, Wen-Hung; Ho, Hsin-Chun

    2018-02-01

    Acute fish liver intoxication, including hypervitaminosis A and hypervitaminosis D, may result from the ingestion of certain fish livers. The typical symptoms of hypervitaminosis A include nausea, headache, blurred vision, and cutaneous manifestations, such as flushing, vesicles formation, and desquamation. Hypervitaminosis D may result in hypercalcemia. We report a case of acute fish liver intoxication with systemic and cutaneous manifestations. A 63-year-old male presented to the clinic with generalized desquamation and multiple clear-fluid filled flaccid vesicles after eating approximately two fist-sized portions (about 300-400 g) of cooked seerfish (Scomberomorus spp.) liver. Laboratory examination showed a high serum level of vitamin A and D, and hypercalcemia. Fish liver consumption from particular fish may result in acute hypervitaminosis A and D. In patients with skin detachment or blister formation, headache, drowsiness, and other symptoms and signs consistent with hypervitaminosis A and/or hypercalcemia, a history of fish intake should be sought, and a serum level of vitamin A and D should be measured.

  5. Nrf2 activation prevents cadmium-induced acute liver injury

    International Nuclear Information System (INIS)

    Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

    2012-01-01

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H 2 DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice were

  6. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  7. Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.

    Science.gov (United States)

    Shin, So Youn; Jeong, Sook-Hyang; Sung, Pil Soo; Lee, Jino; Kim, Hyung Joon; Lee, Hyun Woong; Shin, Eui-Cheol

    2016-05-01

    Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

  8. The significance of parenchymal changes of acute cellular rejection in predicting chronic liver graft rejection

    NARCIS (Netherlands)

    Gouw, ASH; van den Heuvel, MC; van den Berg, AP; Slooff, NJH; de Jong, KP; Poppema, S

    2002-01-01

    Background. Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition

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

    NARCIS (Netherlands)

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

    1990-01-01

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

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

    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

  12. Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands

    NARCIS (Netherlands)

    Dekker, Ruth R.; Schutte, Joke M.; Stekelenburg, Jelle; Zwart, Joost J.; van Roosmalen, Jos

    Objective: To assess maternal death and severe maternal morbidity from acute fatty liver of pregnancy (AFLP) in the Netherlands. Study design: A retrospective study of all cases of maternal mortality in the Netherlands between 1983 and 2006 and all cases of severe maternal morbidity in the

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

    DEFF Research Database (Denmark)

    Wendon, J.; Larsen, Finn Stolze

    2008-01-01

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

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

    NARCIS (Netherlands)

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

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

  15. Adderall Induced Acute Liver Injury: A Rare Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rohini R. Vanga

    2013-01-01

    Full Text Available Adderall (dextroamphetamine/amphetamine is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the case of a 55-year-old woman who developed acute liver failure during the treatment of ADHD with Adderall. She presented to the emergency room with worsening abdominal pain, malaise, and jaundice requiring hospitalization. She had a past history of partial hepatic resection secondary to metastasis from colon cancer which was under remission at the time of presentation. She recovered after intensive monitoring and conservative management. Adderall should be used carefully in individuals with underlying liver conditions.

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

    International Nuclear Information System (INIS)

    Cavet, Madeleine; Balu, Marie; Garel, Catherine; Ducou le Pointe, Hubert; Mitanchez, Delphine; Alexandre, Marie; Renolleau, Sylvain; Pariente, Daniele

    2008-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-10-15

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

  18. In vitro metabolism of [14C]-toluene by human and rat liver microsomes and liver slices

    International Nuclear Information System (INIS)

    Chapman, D.E.; Moore, T.J.; Michener, S.R.; Powis, G.

    1990-01-01

    Toluene metabolites produced by liver microsomes from six human donors included benzylalcohol (Balc), benzaldehyde (Bald) and benzoic acid (Bacid). Microsomes from only one human donor metabolized toluene to p-cresol and o-cresol. Human liver microsomes also metabolized Balc to Bald. Balc metabolism required NADPH, was inhibited by carbon monoxide, and was decreased at a buffer pH of 10. Balc metabolism was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P450 is responsible for the in vitro metabolism of Balc by human liver microsomes. Toluene metabolites formed by human liver slices and released into the incubation media included hippuric acid, and Bacid. Cresols or cresol-conjugates were not detected in liver slice incubation media from any human donor. Toluene metabolism by human liver was compared to metabolism by comparable liver preparations from male Fischer F344 rats. Rates of toluene metabolism by human liver microsomes and liver slices were 9-fold and 1.3-fold greater than for rat liver, respectively. Covalent binding of toluene to human liver microsomes and liver slices was 21-fold and 4-fold greater than for comparable rat liver preparations. Covalent binding of toluene to human microsomes required NADPH, was significantly decreased by coincubation with 4 mM cysteine or 4 mM glutathione, and radioactivity associated with microsomes was decreased by subsequent digestion of microsomes with protease. These results suggest that toluene metabolism and covalent binding of toluene are underestimated if the male Fischer 344 rat is used as a model for human toluene metabolism

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    BACKGROUND & AIMS: Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor......-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.......80 (0.76-0.85)). CONCLUSIONS: The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform...

  20. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

    International Nuclear Information System (INIS)

    Ilowski, Maren; Kleespies, Axel; Toni, Enrico N. de; Donabauer, Barbara; Jauch, Karl-Walter; Hengstler, Jan G.; Thasler, Wolfgang E.

    2011-01-01

    Research highlights: → ALR decreases cytochrome c release from mitochondria. → ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. → ALR exerts a liver-specific anti-apoptotic effect. → A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-β, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-β and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

  1. Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Ilowski, Maren [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Kleespies, Axel [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Toni, Enrico N. de [Department of Medicine II, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Donabauer, Barbara [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Jauch, Karl-Walter [Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Hengstler, Jan G. [Leibniz Research Centre for Working Environment and Human Factors, Technical University, Dortmund (Germany); Thasler, Wolfgang E., E-mail: wolfgang.thasler@med.uni-muenchen.de [Liver Regeneration Group, Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany); Department of Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich (Germany)

    2011-01-07

    Research highlights: {yields} ALR decreases cytochrome c release from mitochondria. {yields} ALR protects hepatocytes against apoptosis induction by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. {yields} ALR exerts a liver-specific anti-apoptotic effect. {yields} A possible medical usage of ALR regarding protection of liver cells during apoptosis inducing therapies. -- Abstract: Augmenter of liver regeneration (ALR) is known to support liver regeneration and to stimulate proliferation of hepatocytes. However, it is not known if ALR exerts anti-apoptotic effects in human hepatocytes and whether this protective effect is cell type specific. This is relevant, because compounds that protect the liver against apoptosis without undesired effects, such as protection of metastatic tumour cells, would be appreciated in several clinical settings. Primary human hepatocytes (phH) and organotypic cancer cell lines were exposed to different concentrations of apoptosis inducers (ethanol, TRAIL, anti-Apo, TGF-{beta}, actinomycin D) and cultured with or without recombinant human ALR (rhALR). Apoptosis was evaluated by the release of cytochrome c from mitochondria and by FACS with propidium iodide (PI) staining. ALR significantly decreased apoptosis induced by ethanol, TRAIL, anti-Apo, TGF-{beta} and actinomycin D. Further, the anti-apoptotic effect of ALR was observed in primary human hepatocytes and in HepG2 cells but not in bronchial (BC1), colonic (SW480), gastric (GC1) and pancreatic (L3.6PL) cell lines. Therefore, the hepatotrophic growth factor ALR acts in a liver specific manner with regards to both its mitogenic and its anti-apoptotic effect. Unlike the growth factors HGF and EGF, rhALR acts in a liver specific manner. Therefore, ALR is a promising candidate for further evaluation as a possible hepatoprotective factor in clinical settings.

  2. Circulating mannan-binding lectin, M-, L-, H-ficolin and collectin-liver-1 levels in patients with acute liver failure

    DEFF Research Database (Denmark)

    Laursen, Tea Lund; Sandahl, Thomas D; Støy, Sidsel

    2015-01-01

    BACKGROUND & AIMS: The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL),...

  3. Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

    Science.gov (United States)

    Bacalini, Maria Giulia; Franceschi, Claudio; Gentilini, Davide; Ravaioli, Francesco; Zhou, Xiaoyuan; Remondini, Daniel; Pirazzini, Chiara; Giuliani, Cristina; Marasco, Elena; Gensous, Noémie; Di Blasio, Anna Maria; Ellis, Ewa; Gramignoli, Roberto; Castellani, Gastone; Capri, Miriam; Strom, Stephen; Nardini, Christine; Cescon, Matteo; Grazi, Gian Luca; Garagnani, Paolo

    2018-03-15

    The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt signaling pathways in the aging of human liver.

  4. Human germline hedgehog pathway mutations predispose to fatty liver.

    Science.gov (United States)

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2 +/- ) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 +/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 +/- mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  5. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis.

    Science.gov (United States)

    Markwardt, Daniel; Holdt, Lesca; Steib, Christian; Benesic, Andreas; Bendtsen, Flemming; Bernardi, Mauro; Moreau, Richard; Teupser, Daniel; Wendon, Julia; Nevens, Frederik; Trebicka, Jonel; Garcia, Elisabet; Pavesi, Marco; Arroyo, Vicente; Gerbes, Alexander L

    2017-10-01

    The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8-49.7), HRS (odds ratio, 4.2; 95% CI, 1.2-14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3-25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90-day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1-4.7) and for NGAL of 1.9 (95% CI, 1.5-2.4). Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232-1241). © 2017 by the American Association for the Study of Liver Diseases.

  6. Antithrombin III is associated with acute liver failure in patients with end-stage heart failure undergoing mechanical circulatory support.

    Science.gov (United States)

    Hoefer, Judith; Ulmer, Hanno; Kilo, Juliane; Margreiter, Raimund; Grimm, Michael; Mair, Peter; Ruttmann, Elfriede

    2017-06-01

    There are few data on the role of liver dysfunction in patients with end-stage heart failure supported by mechanical circulatory support. The aim of our study was to investigate predictors for acute liver failure in patients with end-stage heart failure undergoing mechanical circulatory support. A consecutive 164 patients with heart failure with New York Heart Association class IV undergoing mechanical circulatory support were investigated for acute liver failure using the King's College criteria. Clinical characteristics of heart failure together with hemodynamic and laboratory values were analyzed by logistic regression. A total of 45 patients (27.4%) with heart failure developed subsequent acute liver failure with a hospital mortality of 88.9%. Duration of heart failure, cause, cardiopulmonary resuscitation, use of vasopressors, central venous pressure, pulmonary capillary wedge pressure, pulmonary pulsatility index, cardiac index, and transaminases were not significantly associated with acute liver failure. Repeated decompensation, atrial fibrillation (P failure in univariate analysis only. In multivariable analysis, decreased antithrombin III was the strongest single measurement indicating acute liver failure (relative risk per %, 0.84; 95% confidence interval, 0.77-0.93; P = .001) and remained an independent predictor when adjustment for the Model for End-Stage Liver Disease score was performed (relative risk per %, 0.89; 95% confidence interval, 0.80-0.99; P = .031). Antithrombin III less than 59.5% was identified as a cutoff value to predict acute liver failure with a corresponding sensitivity of 81% and specificity of 87%. In addition to the Model for End-Stage Liver Disease score, decreased antithrombin III activity tends to be superior in predicting acute liver failure compared with traditionally thought predictors. Antithrombin III measurement may help to identify patients more precisely who are developing acute liver failure during mechanical

  7. Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems.

    Science.gov (United States)

    Lee-Montiel, Felipe T; George, Subin M; Gough, Albert H; Sharma, Anup D; Wu, Juanfang; DeBiasio, Richard; Vernetti, Lawrence A; Taylor, D Lansing

    2017-10-01

    This article describes our next generation human Liver Acinus MicroPhysiology System (LAMPS). The key demonstration of this study was that Zone 1 and Zone 3 microenvironments can be established by controlling the oxygen tension in individual devices over the range of ca. 3 to 13%. The oxygen tension was computationally modeled using input on the microfluidic device dimensions, numbers of cells, oxygen consumption rates of hepatocytes, the diffusion coefficients of oxygen in different materials and the flow rate of media in the MicroPhysiology System (MPS). In addition, the oxygen tension was measured using a ratiometric imaging method with the oxygen sensitive dye, Tris(2,2'-bipyridyl) dichlororuthenium(II) hexahydrate (RTDP) and the oxygen insensitive dye, Alexa 488. The Zone 1 biased functions of oxidative phosphorylation, albumin and urea secretion and Zone 3 biased functions of glycolysis, α1AT secretion, Cyp2E1 expression and acetaminophen toxicity were demonstrated in the respective Zone 1 and Zone 3 MicroPhysiology System. Further improvements in the Liver Acinus MicroPhysiology System included improved performance of selected nonparenchymal cells, the inclusion of a porcine liver extracellular matrix to model the Space of Disse, as well as an improved media to support both hepatocytes and non-parenchymal cells. In its current form, the Liver Acinus MicroPhysiology System is most amenable to low to medium throughput, acute through chronic studies, including liver disease models, prioritizing compounds for preclinical studies, optimizing chemistry in structure activity relationship (SAR) projects, as well as in rising dose studies for initial dose ranging. Impact statement Oxygen zonation is a critical aspect of liver functions. A human microphysiology system is needed to investigate the impact of zonation on a wide range of liver functions that can be experimentally manipulated. Because oxygen zonation has such diverse physiological effects in the liver, we

  8. Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

    Science.gov (United States)

    Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

    2018-06-01

    As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  9. Cocktail of chemical compounds robustly promoting cell reprogramming protects liver against acute injury

    Directory of Open Access Journals (Sweden)

    Yuewen Tang

    2017-02-01

    Full Text Available Abstract Tissue damage induces cells into reprogramming-like cellular state, which contributes to tissue regeneration. However, whether factors promoting the cell reprogramming favor tissue regeneration remains elusive. Here we identified combination of small chemical compounds including drug cocktails robustly promoting in vitro cell reprogramming. We then administrated the drug cocktails to mice with acute liver injuries induced by partial hepatectomy or toxic treatment. Our results demonstrated that the drug cocktails which promoted cell reprogramming in vitro improved liver regeneration and hepatic function in vivo after acute injuries. The underlying mechanism could be that expression of pluripotent genes activated after injury is further upregulated by drug cocktails. Thus our study offers proof-of-concept evidence that cocktail of clinical compounds improving cell reprogramming favors tissue recovery after acute damages, which is an attractive strategy for regenerative purpose.

  10. Isolation and characterization of adult human liver progenitors from ischemic liver tissue derived from therapeutic hepatectomies.

    Science.gov (United States)

    Stachelscheid, Harald; Urbaniak, Thomas; Ring, Alexander; Spengler, Berlind; Gerlach, Jörg C; Zeilinger, Katrin

    2009-07-01

    Recent evidence suggests that progenitor cells in adult tissues and embryonic stem cells share a high resistance to hypoxia and ischemic stress. To study the ischemic resistance of adult liver progenitors, we characterized remaining viable cells in human liver tissue after cold ischemic treatment for 24-168 h, applied to the tissue before cell isolation. In vitro cultures of isolated cells showed a rapid decline of the number of different cell types with increasing ischemia length. After all ischemic periods, liver progenitor-like cells could be observed. The comparably small cells exhibited a low cytoplasm-to-nucleus ratio, formed densely packed colonies, and showed a hepatobiliary marker profile. The cells expressed epithelial cell adhesion molecule, epithelial-specific (CK8/18) and biliary-specific (CK7/19) cytokeratins, albumin, alpha-1-antitrypsin, cytochrome-P450 enzymes, as well as weak levels of hepatocyte nuclear factor-4 and gamma-glutamyl transferase, but not alpha-fetoprotein or Thy-1. In vitro survival and expansion was facilitated by coculture with mouse embryonic fibroblasts. Hepatic progenitor-like cells exhibit a high resistance to ischemic stress and can be isolated from human liver tissue after up to 7 days of ischemia. Ischemic liver tissue from various sources, thought to be unsuitable for cell isolation, may be considered as a prospective source of hepatic progenitor cells.

  11. Acute Liver Failure: Pathophysiologic Basis, and The Current and Emerging Therapies

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    Graziella Privitera

    2014-05-01

    Full Text Available Acute liver failure (ALF is a devastating condition that occurs in patients who previously had a normal liver. Although the outcome of patients with ALF has improved, without liver transplantation (LT mortality rates remain in the range of 35-50% in different geographical areas and therefore, its treatment remains an unmet need. In the Western world toxic liver injury from acetaminophen remains one of the common causes but, in the East, hepatitis of unknown aetiology remains the most common cause. Treatment options are limited to meticulous attention to multi-organ support, use of N-acetyl cysteine, judicious use of antibiotics, and timely LT. This review describes the state-of-the-art techniques in the issues related to prognosis, outcome, and treatment of this devastating syndrome.

  12. Co-ordinate but disproportionate activation of apoptotic, regenerative and inflammatory pathways characterizes the liver response to acute amebic infection.

    Science.gov (United States)

    Pelosof, Lorraine C; Davis, Paul H; Zhang, Zhi; Zhang, Xiaochun; Stanley, Samuel L

    2006-03-01

    The liver has the remarkable ability to respond to injury with repair and regeneration. The protozoan parasite Entamoeba histolytica is the major cause of liver abscess worldwide. We report a transcriptional analysis of the response of mouse liver to E. histolytica infection, the first study looking at acute liver infection by a non-viral pathogen. Focusing on early time points, we identified 764 genes with altered transcriptional levels in amebic liver abscess. The response to infection is rapid and complex, with concurrent increased expression of genes linked to host defence through IL-1, TLR2, or interferon-induced pathways, liver regeneration via activation of IL-6 pathways, and genes associated with programmed cell death possibly through TNFalpha or Fas pathways. A comparison of amebic liver infection with the liver response to partial hepatectomy or toxins reveals striking similarities between amebic liver abscess and non-infectious injury in key components of the liver regeneration pathways. However, the response in amebic liver abscess is biased towards apoptosis when compared with acute liver injury from hepatectomy, toxins, or other forms of liver infection. E. histolytica infection of the liver simultaneously activates inflammatory, regenerative and apoptotic pathways, but the sum of these early responses is biased towards programmed cell death.

  13. ASOTHEMIA EFFECT UPON THE LIVER ARGINASE ACTIVITY IN THE ACUTE KIDNEY DAMAGE

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    Jelena Djordjevic

    2002-07-01

    Full Text Available The acute damage of the kidney function leads to an outstanding disbalance of many homeostatic mechanisms in the organism that emerges as a consequence of the reduced glomerulic filtration and the accompanying oliguria. This conditions the emergence of asothemia, that is, the state caracterized by an increase of the level of urea, creatinine and other ureic toxins in the blood. The results of the previous exami-nations show that the acute renal insufficiency is a disturbance accompanied with ac-celerated protein catabolism. The urea is a terminal product of the protein catabolism whose synthesis is mainly taking place in the liver; that is why the research aimed at examining the liver arginase activity, terminal enzyme in the urea synthesis cycle in various experimental models of the acute renal insufficiency. The acute asothemia is experimentally caused upon the male Spraque Dawlly rats by means of two models, namely, the model of bilateral binding of the urethra (BPU and the clycerolic model. The arginase activity in the liver tissue homogenate is measured by the Porembsky and Cedra method on the basis of the liberated ornithine liberation. In the plasma of the experimental animals the level of urea and creatinine was measured for the sake of estimating the renal function. In both the models of the acute kidney damage there was a considerable increase of the urea and creatinine concentration in the plasma (p<0,001 which is followed by a significant increase of the hepatic arginase activity with respect to the control group of the animals. On the basis of the obtained results it can be conclude that asothemia in the acute renal insufficiency is followed by an in-crease in the liver arginase activity.

  14. Aberrant GSTP1 promoter methylation predicts short-term prognosis in acute-on-chronic hepatitis B liver failure.

    Science.gov (United States)

    Gao, S; Sun, F-K; Fan, Y-C; Shi, C-H; Zhang, Z-H; Wang, L-Y; Wang, K

    2015-08-01

    Glutathione-S-transferase P1 (GSTP1) methylation has been demonstrated to be associated with oxidative stress induced liver damage in acute-on-chronic hepatitis B liver failure (ACHBLF). To evaluate the methylation level of GSTP1 promoter in acute-on-chronic hepatitis B liver failure and determine its predictive value for prognosis. One hundred and five patients with acute-on-chronic hepatitis B liver failure, 86 with chronic hepatitis B (CHB) and 30 healthy controls (HC) were retrospectively enrolled. GSTP1 methylation level in peripheral mononuclear cells (PBMC) was detected by MethyLight. Clinical and laboratory parameters were obtained. GSTP1 methylation levels were significantly higher in patients with acute-on-chronic hepatitis B liver failure (median 16.84%, interquartile range 1.83-59.05%) than those with CHB (median 1.25%, interquartile range 0.48-2.47%; P chronic hepatitis B liver failure group, nonsurvivors showed significantly higher GSTP1 methylation levels (P chronic hepatitis B liver failure, GSTP1 methylation showed significantly better predictive value than MELD score [area under the receiver operating characteristic curve (AUC) 0.89 vs. 0.72, P chronic hepatitis B liver failure and shows high predictive value for short-term mortality. It might serve as a potential prognostic marker for acute-on-chronic hepatitis B liver failure. © 2015 John Wiley & Sons Ltd.

  15. Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.

    Science.gov (United States)

    Wen, Zongmei; Lei, Zhen; Yao, Lu; Jiang, Ping; Gu, Tao; Ren, Feng; Liu, Yan; Gou, Chunyan; Li, Xiuhui; Wen, Tao

    2016-09-29

    Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.

  16. Human models of acute lung injury

    Directory of Open Access Journals (Sweden)

    Alastair G. Proudfoot

    2011-03-01

    Full Text Available Acute lung injury (ALI is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

  17. Spectral Electroencephalogram Analysis for the Evaluation of Encephalopathy Grade in Children With Acute Liver Failure.

    Science.gov (United States)

    Press, Craig A; Morgan, Lindsey; Mills, Michele; Stack, Cynthia V; Goldstein, Joshua L; Alonso, Estella M; Wainwright, Mark S

    2017-01-01

    Spectral electroencephalogram analysis is a method for automated analysis of electroencephalogram patterns, which can be performed at the bedside. We sought to determine the utility of spectral electroencephalogram for grading hepatic encephalopathy in children with acute liver failure. Retrospective cohort study. Tertiary care pediatric hospital. Patients between 0 and 18 years old who presented with acute liver failure and were admitted to the PICU. None. Electroencephalograms were analyzed by spectral analysis including total power, relative δ, relative θ, relative α, relative β, θ-to-Δ ratio, and α-to-Δ ratio. Normal values and ranges were first derived using normal electroencephalograms from 70 children of 0-18 years old. Age had a significant effect on each variable measured (p liver failure were available for spectral analysis. The median age was 4.3 years, 14 of 33 were male, and the majority had an indeterminate etiology of acute liver failure. Neuroimaging was performed in 26 cases and was normal in 20 cases (77%). The majority (64%) survived, and 82% had a good outcome with a score of 1-3 on the Pediatric Glasgow Outcome Scale-Extended at the time of discharge. Hepatic encephalopathy grade correlated with the qualitative visual electroencephalogram scores assigned by blinded neurophysiologists (rs = 0.493; p encephalopathy was correlated with a total power of less than or equal to 50% of normal for children 0-3 years old, and with a relative θ of less than or equal to 50% normal for children more than 3 years old (p > 0.05). Spectral electroencephalogram classification correlated with outcome (p encephalopathy and correlates with outcome. Spectral electroencephalogram may allow improved quantitative and reproducible assessment of hepatic encephalopathy grade in children with acute liver failure.

  18. High serum soluble CD30 does not predict acute rejection in liver transplant patients.

    Science.gov (United States)

    Matinlauri, I; Höckerstedt, K; Isoniemi, H

    2006-12-01

    Increased pre- and posttransplantation values of soluble CD30 (sCD30) have been shown to be associated with acute kidney transplant rejection. We sought to study whether high sCD30 could predict rejection early after liver transplantation. The study population included 54 consecutive liver transplant patients, whose samples were collected before liver transplantation and at discharge, which was at a mean time of 3 weeks after transplantation. During the first 6 months posttransplantation, 22 patients experienced an acute rejection episode. Serum sCD30 concentrations were measured by an enzyme-linked immunoassay; changes in serum sCD30 levels posttransplantation were also expressed as relative values compared with pretransplantation results. Liver patients before transplantation displayed higher serum sCD30 values compared with healthy controls: mean values +/- SD were 93 +/- 58 IU/mL vs 17 +/- 8 IU/mL, respectively. At 3 weeks after transplantation the mean sCD30 concentration in liver transplant patients decreased to 59 +/- 42 IU/mL (P = .005). The mean pretransplantation serum sCD30 value was slightly lower among rejecting vs nonrejecting patients: 78 +/- 43 IU/mL vs 104 +/- 65 IU/mL (P = NS). Posttransplantation values in both groups decreased significantly: 47 +/- 34 IU/mL in patients with rejection (P = .014) vs 69 +/- 45 IU/mL in patients without rejection (P = .012). The relative value at 3 weeks posttransplantation decreased slightly more among patients with vs without rejection (70% vs 88%; NS). No correlation was found between serum sCD30 and anti-HLA class I antibodies or crossmatch positivity. In conclusion, neither pre- nor posttransplantation sCD30 levels were associated with acute rejection in liver transplant patients.

  19. Morphology and some biomechanical properties of human liver and spleen

    Czech Academy of Sciences Publication Activity Database

    Stingl, J.; Bača, V.; Čech, V.; Kovanda, J.; Kovandová, H.; Mandys, Václav; Rejmontová, J.; Sosna, B.

    2002-01-01

    Roč. 24, - (2002), s. 285-289 ISSN 0930-1038 Institutional research plan: CEZ:AV0Z5039906 Keywords : Human liver and spleen Subject RIV: FE - Other Internal Medicine Disciplines Impact factor: 0.252, year: 2002

  20. Revisiting acute liver injury associated with herbalife products.

    Science.gov (United States)

    Appelhans, Kristy; Smith, Casey; Bejar, Ezra; Henig, Y Steve

    2011-10-27

    In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.

  1. Prognostic factors for patients with hepatitis B virus-related acute-on-chronic liver failure

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    LI Ying

    2017-03-01

    Full Text Available ObjectiveTo investigate the prognostic factors for patients with hepatitis B virus-related acute-on-chronic liver failure, and to provide a basis for clinical diagnosis and treatment. MethodsA total of 172 patients with hepatitis B virus (HBV-related acute-on-chronic liver failure who were admitted to The First Hospital of Jilin University from January 1, 2006 to January 1, 2016 and had complete medical records and follow-up data were enrolled, and a retrospective analysis was performed for their clinical data and laboratory markers to determine prognostic factors. The independent-samples t test was used for comparison of continuous data between groups, the chi-square test was used for comparison of categorical data between groups, and a multivariate logistic regression analysis was performed for the indices determined to be statistically significant by the univariate analysis to screen out independent risk factors for the prognosis of patients with HBV-related acute-on-chronic liver failure. ResultsThe multivariate logistic regression analysis was performed for the indices determined to be statistically significant by the univariate analysis, and the results showed that the prognostic factors were total bilirubin (TBil, prothrombin time activity (PTA, Na+, total cholesterol (TC, Child-Turcotte-Pugh (CTP score, age ≥50 years, the presence of liver cirrhosis, bilirubin-enzyme separation, and complications. The multivariate regression analysis was performed for the complications determined to affect prognosis by the univariate analysis, and the results showed that the complications as risk factors were hepatic encephalopathy, hepatorenal syndrome, and infection. ConclusionTBil, PTA, Na+, TC, CTP score, age ≥50 years, the presence of liver cirrhosis, bilirubin-enzyme separation, and complications are independent risk factors for the prognosis of patients with HBV-related acute-on-chronic liver failure. Liver failure patients with hepatic

  2. Acute liver failure in a term neonate after repeated paracetamol administration

    OpenAIRE

    Bucaretchi, Fabio; Fernandes, Carla Borrasca; Branco, Maira Migliari; Capitani, Eduardo Mello De; Hyslop, Stephen; Caldas, Jamil Pedro S.; Moreno, Carolina Araujo; Porta, Gilda

    2014-01-01

    Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L), hypoglycemia (18mg/dL), increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L) and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL)...

  3. Acute kidney injury in liver cirrhosis: new definition and application

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    Florence Wong

    2016-12-01

    Full Text Available The traditional diagnostic criteria of renal dysfunction in cirrhosis are a 50% increase in serum creatinine (SCr with a final value above 1.5 mg/dL. This means that patients with milder degrees of renal dysfunction are not being diagnosed, and therefore not offered timely treatment. The International Ascites Club in 2015 adapted the term acute kidney injury (AKI to represent acute renal dysfunction in cirrhosis, and defined it by an increase in SCr of 0.3 mg/dL (26.4 µmoL/L in <48 hours, or a 50% increase in SCr from a baseline within ≤3 months. The severity of AKI is described by stages, with stage 1 represented by these minimal changes, while stages 2 and 3 AKI by 2-fold and 3-fold increases in SCr respectively. Hepatorenal syndrome (HRS, renamed AKI-HRS, is defined by stage 2 or 3 AKI that fulfils all other diagnostic criteria of HRS. Various studies in the past few years have indicated that these new diagnostic criteria are valid in the prediction of prognosis for patients with cirrhosis and AKI. The future in AKI diagnosis may include further refinements such as inclusion of biomarkers that can identify susceptibility for AKI, differentiating the various prototypes of AKI, or track its progression.

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

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    Hessel Franz P

    2006-10-01

    Full Text Available Abstract Background Acute-on-chronic liver failure (ACLF is a life threatening acute decompensation of a pre-existing chronic liver disease. The artificial liver support system MARS is a new emerging therapeutic option possible to be implemented in routine care of these patients. The medical efficacy of MARS has been demonstrated in first clinical studies, but economic aspects have so far not been investigated. Objective of this study was to estimate the cost-effectiveness of MARS. Methods In a clinical cohort trial with a prospective follow-up of 3 years 33 ACLF-patients treated with MARS were compared to 46 controls. Survival, health-related quality of life as well as direct medical costs for in- and outpatient treatment from a health care system perspective were determined. Based on the differences in outcome and indirect costs the cost-effectiveness of MARS expressed as incremental costs per life year gained and incremental costs per QALY gained was estimated. Results The average initial intervention costs for MARS were 14600 EUR per patient treated. Direct medical costs over 3 years follow up were overall 40000 EUR per patient treated with MARS respectively 12700 EUR in controls. The 3 year survival rate after MARS was 52% compared to 17% in controls. Kaplan-Meier analysis of cumulated survival probability showed a highly significant difference in favour of MARS. Incremental costs per life-year gained were 31400 EUR; incremental costs per QALY gained were 47200 EUR. Conclusion The results after 3 years follow-up of the first economic evaluation study of MARS based on empirical patient data are presented. Although high initial treatment costs for MARS occur the significantly better survival seen in this study led to reasonable costs per live year gained. Further randomized controlled trials investigating the medical efficacy and the cost-effectiveness are recommended.

  5. PVA matches human liver in needle-tissue interaction.

    Science.gov (United States)

    de Jong, Tonke L; Pluymen, Loes H; van Gerwen, Dennis J; Kleinrensink, Gert-Jan; Dankelman, Jenny; van den Dobbelsteen, John J

    2017-05-01

    Medical phantoms can be used to study needle-tissue interaction and to train medical residents. The purpose of this research is to study the suitability of polyvinyl alcohol (PVA) as a liver tissue mimicking material in terms of needle-tissue interaction. Insertions into ex-vivo human livers were used for reference. Six PVA samples were created by varying the mass percentage of PVA to water (4m% and 7m%) and the number of freeze-thaw cycles (1, 2 and 3 cycles, 16hours of freezing at -19°C, 8hours of thawing). The inner needle of an 18 Gauge trocar needle with triangular tip was inserted 13 times into each of the samples, using an insertion velocity of 5 mm/s. In addition, 39 insertions were performed in two ex-vivo human livers. Axial forces on the needle were captured during insertion and retraction and characterized by friction along the needle shaft, peak forces, and number of peak forces per unit length. The concentration of PVA and the number of freeze-thaw cycles both influenced the mechanical interaction between needle and specimen. Insertions into 4m% PVA phantoms with 2 freeze-thaw cycles were comparable to human liver in terms of estimated friction along the needle shaft and the number of peak forces. Therefore, these phantoms are considered to be suitable liver mimicking materials for image-guided needle interventions. The mechanical properties of PVA hydrogels can be influenced in a controlled manner by varying the concentration of PVA and the number of freeze-thaw cycles, to mimic liver tissue characteristics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans

    Science.gov (United States)

    McGill, Mitchell R.; Cao, Mengde; Svetlov, Archie; Sharpe, Matthew R.; Williams, C. David; Curry, Steven C.; Farhood, Anwar; Jaeschke, Hartmut; Svetlov, Stanislav I.

    2014-01-01

    Context New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate. Objective Characterize ASS in APAP hepatotoxicity. Methods ASS was measured in plasma from rodents and humans with APAP hepatotoxicity. Results In mice, ASS increased before injury, peaked before ALT, and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all. Conclusions : ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity. PMID:24597531

  7. Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect

    Directory of Open Access Journals (Sweden)

    Helga M. Gretarsdottir

    2018-06-01

    Full Text Available We describe a case of acute liver injury and migratory arthralgia in a patient receiving bicalutamide treatment for prostate cancer. A 67-year-old male with metastatic prostate cancer presented with a 6-day history of migratory arthralgia. He had been undergoing treatment with bicalutamide for 4 months; 3 weeks prior to symptom appearance the bicalutamide dose had been increased. He had no other symptoms. Liver tests and inflammatory markers were markedly elevated. Serology for hepatitis viruses A, B, and C, CMV, and EBV and autoimmune causes were all negative, and an ultrasound of the upper abdomen was normal. There was no history of blood transfusion, intravenous drug abuse, or alcohol abuse. Due to the suspicion of a drug-induced symptomatology, bicalutamide was discontinued and the patient started on 30 mg prednisolone daily. Three weeks later he was symptom free and after 6 weeks his liver tests were almost normal. The Roussel Uclaf Causality Assessment Method (RUCAM suggested a high probability of liver injury. Bicalutamide has very rarely been reported as a causative agent for liver injury and to our knowledge never for migratory polyarthralgia. The migratory polyarthralgia was attributed to bicalutamide due to the absence of other etiological factors and the disappearance of symptoms after discontinuation of the drug. To our knowledge, this is the first published case report of migratory arthralgia and concomitant liver injury attributed to bicalutamide.

  8. A case of moderate liver enzyme elevation after acute acetaminophen overdose despite undetectable acetaminophen level and normal initial liver enzymes.

    Science.gov (United States)

    Bebarta, Vikhyat S; Shiner, Drew C; Varney, Shawn M

    2014-01-01

    Liver function test (LFT) increase is an early sign of acetaminophen (APAP) toxicity. Typically, when an acute overdose patient is evaluated and has an initial undetectable APAP level and normal liver enzymes, the patient is not treated with N-acetylcysteine, and liver enzymes are not expected to increase later. We report a case of moderate LFT increase despite normal LFTs and an undetectable APAP level after delayed presentation of an APAP ingestion. A 22-year-old male with no medical history ingested 15-25 hydrocodone/APAP tablets (5 mg/500 mg). His suicide note and his bunkmate corroborated the overdose time. He arrived at the emergency department 16 hours after ingestion. At that time, his APAP level was enzymes were normal [aspartate transaminase (AST) 31 U/L and alanine transaminase (ALT) 34 U/L]. Twenty-nine hours after ingestion, the psychiatry team obtained LFTs (AST 45, ALT 61). He had persistent nausea and diffuse abdominal pain. On repeat analysis, the APAP level at 36 hours was found to be <10 μg/mL, AST 150, and ALT 204. After 2 more days of increasing LFTs and persistent abdominal pain and nausea, the toxicology department was consulted, the patient was transferred to the medicine department, and intravenous N-acetylcysteine was started 66 hours after ingestion. He was treated for 16 hours and had a significant decline in LFTs and symptom resolution. His prothrombin time, bilirubin, lactate, creatinine, and mental status were normal throughout the admission. Other cases of LFT increase were excluded. Our case report illustrates that a moderate increase in liver transaminase may occur despite an initial undetectable APAP level and normal transaminases after a delayed presentation. In our case, no serious clinical effects were reported.

  9. Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis

    NARCIS (Netherlands)

    Westra, Inge M.; Mutsaers, Henricus A. M.; Luangmonkong, Theerut; Hadi, Mackenzie; Oosterhuis, Dorenda; de Jong, Koert P.; Groothuis, Geny M. M.; Olinga, Peter

    Liver fibrosis is the progressive accumulation of connective tissue ultimately resulting in loss of organ function. Currently, no effective antifibrotics are available due to a lack of reliable human models. Here we investigated the fibrotic process in human precision-cut liver slices (PCLS) and

  10. Hodgkin’s lymphoma coexisting with liver failure secondary to acute on chronic hepatitis B

    Science.gov (United States)

    Palta, Renee; McClune, Amy; Esrason, Karl

    2013-01-01

    Acute on chronic liver failure (ACLF) is rarely the initial manifestation of a malignant process or precipitated by the initiation of anti-viral treatment with a nucleoside or nucleotide agent. We report an unusual case of ACLF temporally associated with initiation of Entecavir for treatment of chronic hepatitis B. Early Hodgkin’s lymphoma (HL) was unmasked with initiation of the anti-viral treatment which may have exacerbated ACLF. To the best of our knowledge, this has not been described in the literature. In reviewing our patients clinical course and liver autopsy, he developed a severe acute exacerbation of his chronic hepatitis B virus coinciding with the institution of antiviral therapy and the underlying HL perhaps modulating the overall degree of hepatic injury. PMID:24303460

  11. Hodgkin's lymphoma coexisting with liver failure secondary to acute on chronic hepatitis B.

    Science.gov (United States)

    Palta, Renee; McClune, Amy; Esrason, Karl

    2013-04-16

    Acute on chronic liver failure (ACLF) is rarely the initial manifestation of a malignant process or precipitated by the initiation of anti-viral treatment with a nucleoside or nucleotide agent. We report an unusual case of ACLF temporally associated with initiation of Entecavir for treatment of chronic hepatitis B. Early Hodgkin's lymphoma (HL) was unmasked with initiation of the anti-viral treatment which may have exacerbated ACLF. To the best of our knowledge, this has not been described in the literature. In reviewing our patients clinical course and liver autopsy, he developed a severe acute exacerbation of his chronic hepatitis B virus coinciding with the institution of antiviral therapy and the underlying HL perhaps modulating the overall degree of hepatic injury.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... 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...... MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P

  13. Antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease.

    Science.gov (United States)

    Martí-Carvajal, Arturo J; Solà, Ivan

    2015-06-09

    Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. People with liver disease frequently have haemostatic abnormalities such as hyperfibrinolysis. Therefore, antifibrinolytic amino acids have been proposed to be used as supplementary interventions alongside any of the primary treatments for upper gastrointestinal bleeding in people with liver diseases. This is an update of this Cochrane review. To assess the beneficial and harmful effects of antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease. We searched The Cochrane Hepato-Biliary Controlled Trials Register (February 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2 of 12, 2015), MEDLINE (Ovid SP) (1946 to February 2015), EMBASE (Ovid SP) (1974 to February 2015), Science Citation Index EXPANDED (1900 to February 2015), LILACS (1982 to February 2015), World Health Organization Clinical Trials Search Portal (accessed 26 February 2015), and the metaRegister of Controlled Trials (accessed 26 February 2015). We scrutinised the reference lists of the retrieved publications. Randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. Observational studies for assessment of harms. We planned to summarise data from randomised clinical trials using standard Cochrane methodologies and assessed according to the GRADE approach. We found no randomised clinical trials assessing antifibrinolytic amino acids for treating upper gastrointestinal bleeding in people with acute or chronic liver disease. We did not identify quasi-randomised, historically controlled, or observational studies in which we could assess harms. This updated Cochrane review identified no randomised clinical trials assessing the benefits and harms of antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or

  14. Influence of matrix nature on the functional efficacy of biomedical cell product for the regeneration of damaged liver (experimental model of acute liver failure

    Directory of Open Access Journals (Sweden)

    S. V. Gautier

    2017-01-01

    Full Text Available Aim. A comparative analysis of the functional efficacy of biomedical cell products (BMCP for the regeneration of damaged liver based on biopolymer scaffolded porous and hydrogel matrices was performed on the experimental model of acute liver failure. Materials and methods. Matrices allowed for clinical use were employed for BMCP in the form of a sponge made from biopolymer nanostructured composite material (BNCM based on a highly purified bacterial copolymers of poly (β-hydroxybutyrate-co-β-oxyvalerate and polyethylene glycol and a hydrogel matrix from biopolymer microheterogeneous collagen-containing hydrogel (BMCH. Cellular component of BMCP was represented by liver cells and multipotent mesenchymal bone marrow stem cells. The functional efficacy of BMCP for the regeneration of damaged liver was evaluated on the experimental model of acute liver failure in Wistar rats (n = 40 via biochemical, morphological, and immunohistochemical methods. Results. When BMCP was implanted to regenerate the damaged liver on the basis of the scaffolded BNCM or hydrogel BMCH matrices, the lethality in rats with acute liver failure was absent; while in control it was 66.6%. Restoration of the activity of cytolytic enzyme levels and protein-synthetic liver function began on day 9 after modeling acute liver failure, in contrast to the control group, where recovery occurred only by days 18–21. Both matrices maintained the viability and functional activity of liver cells up to 90 days with the formation of blood vessels in BMCP. The obtained data confirm that scaffolded BNCM matrix and hydrogel BMCH matrix retain for a long time (up to 90 days the vital activity of the adherent cells in the BMCP composition, which allows using them to correct acute liver failure. At the same time, hydrogel matrix due to the presence of bioactive components contributes to the creation of the best conditions for adhesion and cell activity which accelerate the regeneration processes

  15. Acute humoral rejection and C4d immunostaining in ABO blood type-incompatible liver transplantation.

    Science.gov (United States)

    Haga, Hironori; Egawa, Hiroto; Fujimoto, Yasuhiro; Ueda, Mikiko; Miyagawa-Hayashino, Aya; Sakurai, Takaki; Okuno, Tomoko; Koyanagi, Itsuko; Takada, Yasutsugu; Manabe, Toshiaki

    2006-03-01

    Complement C4d deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in kidney and other solid organ transplantation. The correlation of C4d deposits and humoral rejection in liver transplants, however, is not well understood. We investigated the C4d immunostaining pattern in 34 patients whose liver biopsy was taken within the first 3 postoperative weeks for suspected acute rejection after ABO blood type-incompatible liver transplantation. The staining pattern was classified as positive (portal stromal staining), indeterminate (endothelial staining only), and negative (no staining). Positive C4d immunostaining was seen in 17 (50%) patients and was significantly associated with high (x64 or more) postoperative antidonor A/B antibody (immunoglobulin M (IgM)) titers (88 vs. 35%, P = 0.002) and poorer overall survival rate (41 vs. 88%, P = 0.007). Ten of 11 (91%) cases with histological acute humoral rejection (periportal edema and necrosis (PEN) or portal hemorrhagic edema) were positive for C4d, all of which showed high postoperative antibody titers. The other histologies associated with C4d positivity was purulent cholangitis (n = 4), coagulative hepatocyte necrosis (n = 1), acute cellular rejection (n = 1), and hepatocanalicular cholestasis (n = 1). Full clinical recovery was observed in only 6 of 17 (35%) C4d-positive patients, and tended to be associated with a lower rejection activity index (RAI). In conclusion, our study indicates that C4d deposits in the portal stroma can be a hallmark of acute humoral rejection in ABO-incompatible liver transplantation, and allograft damage can be reversible in a minority of cases. Copyright 2006 AASLD

  16. Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients.

    Science.gov (United States)

    Guo, Ruo-Mi; Li, Qing-Ling; Zhong, Li-Ru; Guo, Yu; Jiao, Ju; Chen, Shao-Qiong; Wang, Jin; Zhang, Yong

    2018-06-01

    Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3 years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5 years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n = 14), and the plasma ammonia levels ranged from 68.63 to 192.16 μmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance.

  17. [Severe toxic liver failure after acute poisoning with paracetamol, ferrous sulphate and naproxen].

    Science.gov (United States)

    Adamek, Robert; Wilczek, Lech; Krupiński, Bogusław

    2004-01-01

    We present the case of 20-year-old woman intoxicated with mixed drugs, composed of paracetamol (acetaminophen), ferrous sulphate, naproxen and benzodiazepines. Acute toxic liver damage with clinical symptoms of coma resolved at the patient. Lack of the past history doesn't let to specific therapy and systemic complications. In this data we confirm, that past history, clinical symptoms and laboratory results are needed in designing a treatment strategy.

  18. Endovascular Treatment of Acute Portal Vein Thrombosis After Liver Transplantation in a Child

    International Nuclear Information System (INIS)

    Carnevale, Francisco Cesar; Borges, Marcus Vinicius; Moreira, Airton Mota; Cerri, Giovanni Guido; Maksoud, Joao Gilberto

    2006-01-01

    Although operative techniques in hepatic transplantation have reduced the time and mortality on waiting lists, the rate of vascular complications associated with these techniques has increased. Stenosis or thrombosis of the portal vein is an infrequent complication, and if present, surgical treatment is considered the traditional management. This article describes a case of acute portal vein thrombosis after liver transplantation from a living donor to a child managed by percutaneous techniques

  19. Outcomes of Children With and Without Hepatic Encephalopathy From the Pediatric Acute Liver Failure Study Group.

    Science.gov (United States)

    Ng, Vicky L; Li, Ruosha; Loomes, Kathleen M; Leonis, Mike A; Rudnick, David A; Belle, Steven H; Squires, Robert H

    2016-09-01

    Hepatic encephalopathy (HE) is challenging to identify in children with acute liver failure and was not a requirement for enrollment into the Pediatric Acute Liver Failure Study Group (PALFSG). The outcomes of PALFSG participants presenting with and without HE are presented. PALFSG participants were classified based on daily assessment of HE during the first 7 days following study enrollment: group 1-never developed HE; group 2-no HE at enrollment with subsequent HE development; and group 3-HE at study enrollment. Clinical and biochemical parameters and outcomes of death, spontaneous recovery, or liver transplantation were compared between groups. Data from 769 PALFSG (54% boys; median age 4.2 years; range 0-17.9 years) participants were analyzed, with 277 in group 1 (36%), 83 in group 2 (11%), and 409 in group 3 (53%). Mortality occurred in 11% of all participants and was highest among group 3 participants who demonstrated persistent grade III-IV HE (55%) or showed progression of HE (26%). Eleven (4%) group 1 participants died within 21 days of enrollment. Spontaneous recovery was highest in group 1 (79%) and lowest in group 2 (25%; P liver failure prognostication schema are needed.

  20. Etiologies and Outcomes of Acute Liver Failure in a Spanish Community

    Directory of Open Access Journals (Sweden)

    Emilio Fábrega

    2013-01-01

    Full Text Available Previous retrospective study (1992 to 2000 performed in Spain showed that drug toxicity, viral hepatitis, and indeterminate etiology were the most prevalent causes of acute liver failure (ALF. In the last decade, there is no information about ALF in our country. For these reasons we analyze retrospectively, in a ten-year period (2000 to 2010, the presumed causes, clinical characteristics, course, and outcome of ALF in a Spanish community. Causes of ALF were indeterminate in 4 patients (24%, acute hepatitis B infection in 4 patients (24%, drug or toxic reactions in 4 patients (24%, including one case of acetaminophen overdose, followed by miscellaneous causes. The overall short-term survival (6 weeks after admission was 65%. Liver transplantation was performed in 11 patients with a survival of 82%. Despite fulfilling criteria, 2 patients were not transplanted because of contraindications; they both died. In summary, acute hepatitis B and indeterminate cause are still being the most frequent causes of ALF in our region, and patients with ALF have an excellent chance of survival after emergency liver transplantation. Acetaminophen overdose still represents a very rare cause of ALF in our community.

  1. Acute liver allograft antibody-mediated rejection:an inter-institutional study of significant histopathological features

    OpenAIRE

    O'Leary, Jacqueline G; Shiller, S Michelle; Bellamy, Christopher; Nalesnik, Michael A; Kaneku, Hugo; Jennings, Linda W; Isse, Kumiko; Terasaki, Paul I; Klintmalm, Göran B; Demetris, Anthony J

    2014-01-01

    Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, specific features that could be used: a) for a generalizable scoring system; and b) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases ...

  2. Phosphorus-31 spectroscopic imaging of the human liver

    International Nuclear Information System (INIS)

    Biran, M.; Raffard, G.; Canioni, P.; Kien, P.

    1993-01-01

    During the last decade, progresses in the field of nuclear magnetic resonance spectroscopy (M.R.S.), have allowed the metabolic studies of complex biological systems. Since the coming out of whole body magnets, clinical applications are possible; they utilize magnetic field gradients coupled with selective pulse sequences. Study of the phosphorylated metabolism of human liver can be performed with sequences as ISIS, FROGS or 1D-CSI. But they present some disadvantages (for instance contamination by phosphocreatine from muscle). In the present work, we have studied the human liver in vivo by 31 P spectroscopic imaging. Several spectra could be acquired with only one acquisition. This study has needed the building of radiofrequency coils (surface coils), specially designed for liver observation (15 cm diameter 31 P coil and 19 cm diameter proton coil, both transmitter and receiver coils). Preliminary studies have been done on a phantom followed by in vivo measurements on healthy subject livers. We have obtained localized 31 P N.M.R. spectra corresponding to different voxels within the hepatic tissue. The conditions of acquisition of spectra and the problems related to the saturation of phosphorylated metabolite signals (in particular phosphodiesters) are discussed. (author). 5 figs., 15 refs

  3. Analysis of iron storage proteins in chicken liver and spleen tissues in comparison with human liver ferritin by Moessbauer spectroscopy

    International Nuclear Information System (INIS)

    Oshtrakh, M.I.; Milder, O.B.; Semionkin, V.A.; Malakheeva, L.I.; Prokopenko, P.G.

    2006-01-01

    Characterization of iron storage proteins in liver and spleen from normal chicken and chicken with lymphoid leukemia in comparison with human liver ferritin were considered by Moessbauer spectroscopy (preliminary results). Small differences in Moessbauer hyperfine parameters for both normal and lymphoid leukemia chicken liver and spleen were observed. The value of quadrupole splitting for human liver ferritin was higher than those for chicken tissues. A decrease of iron content in lymphoid leukemia chicken tissues was also found, however, the reason of this fact (pathology or feeding) was not clear yet. (author)

  4. Acetaminophen (Paracetamol induced acute liver failure – A social problem in an era of increasing tendency to self-treatment

    Directory of Open Access Journals (Sweden)

    Tadeusz Wróblewski

    2015-12-01

    Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

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

    Directory of Open Access Journals (Sweden)

    Tae Yeob Kim

    Full Text Available To investigate the prevalence, mortalities, and patient characteristics of Acute-on-chronic liver failure (ACLF according to the AARC (Asian Pacific Association for the Study of the Liver ACLF Research Consortium and European Association for the Study of the Liver CLIF-C (Chronic Liver Failure Consortium definitions.We collected retrospective data for 1470 hospitalized patients with chronic liver disease (CLD and acute deterioration between January 2013 and December 2013 from 21 university hospitals in Korea.Of the patients assessed, the prevalence of ACLF based on the AARC and CLIF-C definitions was 9.5% and 18.6%, respectively. The 28-day and 90-day mortality rates were higher in patients with ACLF than in those without ACLF. Patients who only met the CLIF-C definition had significantly lower 28-day and 90-day survival rates than those who only met the AARC definition (68.0% vs. 93.9%, P<0.001; 55.1% vs. 92.4%, P<0.001. Among the patients who had non-cirrhotic CLD, the 90-day mortality of the patients with ACLF was higher than of those without ACLF, although not significant (33.3% vs. 6.0%, P = 0.192. Patients with previous acute decompensation (AD within 1- year had a lower 90-day survival rate than those with AD more than 1 year prior or without previous AD (81.0% vs. 91.9% or 89.4%, respectively, all P<0.001. Patients who had extra-hepatic organ failure without liver failure had a similar 90-day survival rate to those who had liver failure as a prerequisite (57.0% vs. 60.6%, P = 0.391.The two ACLF definitions result in differences in mortality and patient characteristics among ACLF patients. We suggest that non-cirrhotic CLD, previous AD within 1 year, and extra-hepatic organ failure should be included in the ACLF diagnostic criteria. In addition, further studies are necessary to develop a universal definition of ACLF.

  6. Uncoupling and oxidative stress in liver mitochondria isolated from rats with acute iron overload

    Energy Technology Data Exchange (ETDEWEB)

    Pardo Andreu, G.L. [Centro de Quimica Farmaceutica, Departamento de Investigaciones Biomedicas, Ciudad de La Habana (Cuba); Inada, N.M.; Vercesi, A.E. [Universidade Estadual de Campinas, Departamento de Patologia Clinica, Faculdade de Ciencias Medicas, Campinas, SP (Brazil); Curti, C. [Universidade de Sao Paulo, Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, SP (Brazil)

    2009-01-15

    One hypothesis for the etiology of cell damage arising from iron overload is that its excess selectively affects mitochondria. Here we tested the effects of acute iron overload on liver mitochondria isolated from rats subjected to a single dose of i.p. 500 mg/kg iron-dextran. The treatment increased the levels of iron in mitochondria (from 21{+-}4 to 130{+-}7 nmol/mg protein) and caused both lipid peroxidation and glutathione oxidation. The mitochondria of iron-treated rats showed lower respiratory control ratio in association with higher resting respiration. The mitochondrial uncoupling elicited by iron-treatment did not affect the phosphorylation efficiency or the ATP levels, suggesting that uncoupling is a mitochondrial protective mechanism against acute iron overload. Therefore, the reactive oxygen species (ROS)/H{sup +} leak couple, functioning as a mitochondrial redox homeostatic mechanism could play a protective role in the acutely iron-loaded mitochondria. (orig.)

  7. Tacrolimus Aggravated Tube Feeding Syndrome with Acute Renal Failure in a Pediatric Liver Transplant Recipient

    Directory of Open Access Journals (Sweden)

    R. Kula

    2017-01-01

    Full Text Available Acute renal failure can be caused by calcineurin inhibitors (CNIs, due to arteriolopathy and altered tubular function. Within this context, we present the case of a 14-month-old liver transplant recipient who suffered an acute polyuric renal failure during a short episode of hypercaloric feeding. In our case, CNI-induced distal RTA led to nephrocalcinosis and therefore to secondary nephrogenic diabetes insipidus. The diet with high renal solute load consequently resulted in an acute polyuric renal failure with severe hypernatremic dehydration. In conclusion, a hypercaloric diet in children with potentially impaired renal function due to therapy with CNIs requires precise calculation of the potential renal solute load and the associated fluid requirements.

  8. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

    Science.gov (United States)

    Ushijima, Kentarou; Tsuruoka, Shu-ichi; Tsuda, Hidetoshi; Hasegawa, Gohki; Obi, Yuri; Kaneda, Tae; Takahashi, Masaki; Maekawa, Tomohiro; Sasaki, Tomohiro; Koshimizu, Taka-aki; Fujimura, Akio

    2009-01-01

    AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. PMID:19694738

  9. Brain expression of the water channels Aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema

    DEFF Research Database (Denmark)

    Eefsen, Martin; Jelnes, Peter; Schmidt, Lars E

    2010-01-01

    Cerebral edema is a feared complication to acute liver failure (ALF), but the pathogenesis is still poorly understood. The water channels Aquaporin-1 (Aqp1) and -4 (Aqp4) has been associated with brain edema formation in several neuropathological conditions, indicating a possible role of Aqp1 and....../or Aqp4 in ALF mediated brain edema. We induced acute liver injury and hyperammonemia in mice, to evaluate brain edema formation and the parallel expression of Aqp1 and Aqp4 in ALF. Liver injury and hyperammonemia were induced by +D-galactosamine (GLN) plus lipopolysaccharide (LPS) intraperitoneally......(6266) (p edema in mice with ALF....

  10. Liver afferents contribute to water drinking-induced sympathetic activation in human subjects: a clinical trial.

    Directory of Open Access Journals (Sweden)

    Marcus May

    Full Text Available Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (p<0.05 between groups after 30-40 minutes of water drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects.ClinicalTrials.gov NCT01237431.

  11. Liver Afferents Contribute to Water Drinking-Induced Sympathetic Activation in Human Subjects: A Clinical Trial

    Science.gov (United States)

    May, Marcus; Gueler, Faikah; Barg-Hock, Hannelore; Heiringhoff, Karl-Heinz; Engeli, Stefan; Heusser, Karsten; Diedrich, André; Brandt, André; Strassburg, Christian P.; Tank, Jens; Sweep, Fred C. G. J.; Jordan, Jens

    2011-01-01

    Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant) as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant) as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (pwater drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects. Trial Registration ClinicalTrials.gov NCT01237431 PMID:22016786

  12. Hematopoietic growth factors and human acute leukemia.

    Science.gov (United States)

    Löwenberg, B; Touw, I

    1988-10-22

    The study of myelopoietic maturation arrest in acute myeloblastic leukemia (AML) has been eased by availability of the human recombinant hemopoietic growth factors, macrophage colony stimulating factor (M-CSF), granulocyte-(G-CSF), granulocyte-macrophage-(GM-CSF) and multilineage stimulating factor (IL-3). Nonphysiological expansion of the leukemic population is not due to escape from control by these factors. Proliferation in vitro of AML cells is dependent on the presence of one or several factors in most cases. The pattern of factor-dependency does not correlate with morphological criteria in individual cases, and may thus offer a new tool for classification of AML. Overproduction of undifferentiated cells is not due to abnormal expression of receptors for the stimulating factors acting at an immature level. Rather, autocrine secretion of early acting lymphokines maintains proliferation of the leukemic clone. When looking at causes of leukemic dysregulation, yet undefined inhibitors of differentiation probably are of equal importance as dysequilibrated stimulation by lymphokines.

  13. Immune mediated liver failure.

    Science.gov (United States)

    Wang, Xiaojing; Ning, Qin

    2014-01-01

    Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.

  14. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

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    Sathish Kumar Natarajan

    2018-01-01

    Full Text Available Acute fatty liver of pregnancy (AFLP, a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD. The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency.

  15. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

    Science.gov (United States)

    Ibdah, Jamal A.

    2018-01-01

    Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. PMID:29361796

  16. Tumor-Like Liver Abscess Mimicking Malignancy With Lung Metastases in a Patient With Acute Renal Failure: A Case Report.

    Science.gov (United States)

    Wang, Chih Hsin; Sun, Cheuk-Kay; Jiang, Jiunn-Song; Tsai, Ming Hsien

    2016-03-01

    The worldwide incidence of Klebsiella pneumoniae liver abscess (KLA) is increasing. It is important to accurately diagnose this life-threatening disease to provide timely and appropriate treatment. Here we report the case of a 38-year-old man with acute renal failure and a tumor-like liver abscess and septic pulmonary embolism. Initially, his clinical symptoms, laboratory tests, and radiological findings presented equivocal results of malignancy with metastases. Fine needle aspiration of liver tumor was performed, which showed purulent material with a culture positive for K pneumoniae. KLA symptoms are atypical, and radiological findings may mimic a malignancy with tumor necrosis. In some circumstances, liver aspiration biopsy may be necessary to confirm the real etiology, leading to prompt and timely treatment. Moreover, we should be alert for the impression of KLA when facing a diabetic patient with liver mass lesion and acute renal failure.

  17. Interaction of rocuronium with human liver cytochromes P450.

    Science.gov (United States)

    Anzenbacherova, Eva; Spicakova, Alena; Jourova, Lenka; Ulrichova, Jitka; Adamus, Milan; Bachleda, Petr; Anzenbacher, Pavel

    2015-02-01

    Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  18. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

    Science.gov (United States)

    Larsen, Fin Stolze; Schmidt, Lars Ebbe; Bernsmeier, Christine; Rasmussen, Allan; Isoniemi, Helena; Patel, Vishal C; Triantafyllou, Evangelos; Bernal, William; Auzinger, Georg; Shawcross, Debbie; Eefsen, Martin; Bjerring, Peter Nissen; Clemmesen, Jens Otto; Hockerstedt, Krister; Frederiksen, Hans-Jørgen; Hansen, Bent Adel; Antoniades, Charalambos G; Wendon, Julia

    2016-01-01

    Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (pHVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  19. Vitamin K for upper gastrointestinal bleeding in people with acute or chronic liver diseases.

    Science.gov (United States)

    Martí-Carvajal, Arturo J; Solà, Ivan

    2015-06-09

    Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. Several treatments are used for upper gastrointestinal bleeding in people with liver diseases. One of them is vitamin K administration, but it is not known whether it benefits or harms people with acute or chronic liver disease and upper gastrointestinal bleeding. This is an update of this Cochrane review. To assess the beneficial and harmful effects of vitamin K for people with acute or chronic liver disease and upper gastrointestinal bleeding. We searched The Cochrane Hepato-Biliary Controlled Trials Register (February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2 of 12, 2015), MEDLINE (Ovid SP) (1946 to February 2015), EMBASE (Ovid SP) (1974 to February 2015), Science Citation Index EXPANDED (1900 to February 2015), and LILACS (1982 to 25 February 2015). We sought additional randomised trials from two registries of clinical trials: the World Health Organization Clinical Trials Search Portal and the metaRegister of Controlled Trials. We looked through the reference lists of the retrieved publications and review articles. Randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. We considered observational studies for assessment of harms only. \\We aimed to summarise data from randomised clinical trials using Standard Cochrane methodology and assess them according to the GRADE approach. We found no randomised trials on vitamin K for upper gastrointestinal bleeding in people with liver diseases assessing benefits and harms of the intervention. We identified no quasi-randomised studies, historically controlled studies, or observational studies assessing harms. This updated review found no randomised clinical trials of vitamin K for upper gastrointestinal bleeding in people with liver diseases. The benefits and harms of vitamin K need to be tested

  20. Quantitative multivoxel {sup 1}H MR spectroscopy of the brain in children with acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Sijens, Paul E.; Alkefaji, Heyder; Meiners, Linda C.; Oudkerk, Matthijs [University Medical Center Groningen and University of Groningen, Department of Radiology, Beatrix Children' s Hospital, Groningen (Netherlands); Lunsing, Roelineke J. [University Medical Center Groningen and University of Groningen, Department of Child Neurology, Beatrix Children' s Hospital, Groningen (Netherlands); Spronsen, Francjan J. van; Verkade, Henkjan J. [University Medical Center Groningen and University of Groningen, Department of Pediatrics, Beatrix Children' s Hospital, Groningen (Netherlands)

    2008-11-15

    Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P < 0.01; lactate + 33%, P < 0.05) and higher Glx in grey matter (Glx + 125%: P < 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P < 0.05), and negative correlations between grey or white matter Glx and venous pH (P < 0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, {gamma}-glutamyl transpeptidase, alkaline phosphatase). (orig.)

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

    International Nuclear Information System (INIS)

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

    2008-01-01

    Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P < 0.01; lactate + 33%, P < 0.05) and higher Glx in grey matter (Glx + 125%: P < 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P < 0.05), and negative correlations between grey or white matter Glx and venous pH (P < 0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase). (orig.)

  2. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

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

    Directory of Open Access Journals (Sweden)

    Herson Antonio González-Ponce

    2016-10-01

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

  4. Procalcitonin Identifies Cell Injury, Not Bacterial Infection, in Acute Liver Failure.

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    Jody A Rule

    Full Text Available Because acute liver failure (ALF patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD subjects served as controls.Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169. PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001. Subjects with acetaminophen (APAP toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.

  5. Hepatoprotective effect of Scoparia dulcis on carbon tetrachloride induced acute liver injury in mice.

    Science.gov (United States)

    Tsai, Jen-Chieh; Peng, Wen-Huang; Chiu, Tai-Hui; Huang, Shun-Chieh; Huang, Tai-Hung; Lai, Shang-Chih; Lai, Zhen-Rung; Lee, Chao-Ying

    2010-01-01

    This study aims to investigate the hepatoprotective activity and active constituents of the ethanol extract of Scoparia dulcis (SDE). The hepatoprotective effect of SDE (0.1, 0.5 and 1 g/kg) was evaluated on the carbon tetrachloride (CCl(4))-induced acute liver injury. The active constituents were detected by high performance liquid chromatography (HPLC). Mice pretreated orally with SDE (0.5 and 1.0 g/kg) and silymarin (200 mg/kg) for five consecutive days before the administering of a single dose of 0.2% CCl(4) (10 ml/kg of bw, ip) showed a significant inhibition of the increase of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological analyses also showed that SDE (0.5 and 1.0 g/kg) and silymarin reduced the extent of liver lesions induced by CCl(4), including vacuole formation, neutrophil infiltration and necrosis. Moreover, SDE decreased the malondialdehyde (MDA) level and elevated the content of reduced glutathione (GSH) in the liver as compared to those in the CCl(4) group. Furthermore, SDE (0.5 and 1.0 g/kg) enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd) and glutathione-S-transferase (GST). The quantities of active constituents in SDE were about 3.1 mg luteolin/g extract and 1.1 mg apigenin/g extract. The hepatoprotective mechanisms of SDE were likely associated to the decrease in MDA level and increase in GSH level by increasing the activities of antioxidant enzymes such as SOD, GPx, GRd and GST. These results demonstrated that SDE could alleviate CCl(4)-induced acute liver injury in mice.

  6. Study on bone marrow mesenchymal stem cells in repairing of radiation induced acute liver injury of rats

    International Nuclear Information System (INIS)

    Bao Yongxing; Lou Fan; Zhao Huarong; Zhu Huhu; Ma Yan; Wen Hao

    2010-01-01

    Objective: To investigate the role of mesenchymal stem cells in the repair of radiation induced liver injury. Methods: 12 female SD rats were irradiated with 20 Gy 6 MV X-rays on the right lobe of the liver, to establish the model of radiation induced liver injury. The rats were divided randomly into two groups as invention group and control group, and transplanted with 1 ml male mesenchymal suspension or 1 ml normal saline in 4 hours after radiotherapy. The morphological changes of liver were observed. The existence of sex determining gene Y(SRY) and the level of alpha-smooth muscle actin (a-SMA) were detected. Results: Some injury of right lobe liver in two groups were observed, and the injury degree of right lobe liver in intervention group were lower than that of control group. The amount of SRY positive cells in the right lobe liver of intervention group was higher than that in the left lobe liver (t = 3.77, P <0.05). The positive expression rate of a-SMA in right lobe liver of intervention group was lower than that of control group. Conclusions: Acute radiation induced liver injury could lead BMSCs' homing in order to decrease the degree of liver fibrosis. (authors)

  7. Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy.

    Science.gov (United States)

    Brusilow, Saul W; Cooper, Arthur J L

    2011-11-01

    Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen. Case report. Johns Hopkins Hospital. A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated. She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter. Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began

  8. The value of microparticles in detecting acute rejection episodes after liver transplantation.

    Science.gov (United States)

    Morgul, Mehmet Haluk; Splith, Katrin; Leonhardt, Christoph; Raschzok, Nathanael; Reutzel-Selke, Anja; Schmuck, Rosa Bianca; Andreou, Andreas; Atanasov, Georgi; Benzing, Christian; Krenzien, Felix; Hau, Hans-Michael; Felgendreff, Philipp; Klunk, Sergej; Pratschke, Johann; Sauer, Igor Maximillian; Schmelzle, Moritz

    2018-02-01

    Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet. We analyzed the correlation of plasma microparticle levels (MP) with AR. MP (CD4, CD8, CD25, CD31, MHC) of 11 AR patients and 11 controls were analyzed within the first week after transplantation. CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups. MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation.

  9. Acute liver failure following recreational use of psychotropic "head shop" compounds.

    Science.gov (United States)

    Fröhlich, S; Lambe, E; O'Dea, J

    2011-03-01

    The recreational use of the so-called "legal-highs" has been in both the medical and political arena over the last year as a result of the appearance of "head shops" in many towns in Ireland. These shops specialized in selling new psychotropic compounds that circumvented established drug legislation. Little is known about the potentially harmful effects of these substances but case reports suggest a plethora of harmful psychological and physical effects. Our case describes for the first time acute liver failure associated with the ingestion of two of these amphetamine type compounds.

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    Acute liver failure (ALF) is a condition with an unfavourable prognosis. Multiorgan failure and circulatory collapse are frequent causes of death, but cerebral edema and intracranial hypertension (ICH) are also common complications with a high risk of fatal outcome. The underlying pathogenesis has...... been extensively studied and although the development of cerebral edema and ICH is of a complex and multifactorial nature, it is well established that ammonia plays a pivotal role. This review will focus on the effects of hyperammonemia on neurotransmission, mitochondrial function, oxidative stress...

  11. Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

    Directory of Open Access Journals (Sweden)

    Shen Chuan

    2010-08-01

    Full Text Available Abstract Background Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. Case Presentation We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. Conclusions This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important.

  12. Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

    Science.gov (United States)

    2010-01-01

    Background Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. Case Presentation We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. Conclusions This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important. PMID:20707932

  13. Extended normothermic extracorporeal perfusion of isolated human liver after warm ischaemia: a preliminary report.

    Science.gov (United States)

    Bellomo, Rinaldo; Marino, Bruno; Starkey, Graeme; Fink, Michael; Wang, Bao Zhong; Eastwood, Glenn M; Peck, Leah; Young, Helen; Houston, Shane; Skene, Alison; Opdam, Helen; Jones, Robert

    2014-09-01

    Donation after circulatory death (DCD) livers are at markedly increased risk of primary graft dysfunction and biliary tract ischaemia. Normothermic extracorporeal liver perfusion (NELP) may increase the ability to transplant DCD livers and may allow their use for artificial extracorporeal liver support of patients with fulminant liver failure. We conducted two proof-of-concept experiments using human livers after DCD to assess the feasibility and functional efficacy of NELP over an extended period. We applied extracorporeal membrane oxygenation, parenteral nutrition, separate hepatic artery and portal vein perfusion and physiological perfusion pressures to two livers obtained after DCD. We achieved NELP and evidence of liver function (bile production, paracetamol removal and maintenance of normal lactate levels) in both livers; one for 24 hours and the other for 43 hours. Histological examination showed areas of patchy ischaemia but preserved biliary ducts and canaliculi. Our experiments justify further investigations of the feasibility and efficacy of extended DCD liver preservation by ex-vivo perfusion.

  14. Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms With Acute Rejection in Liver Transplant Recipients.

    Science.gov (United States)

    Azarpira, Negar; Namazi, Soha; Malahi, Sayan; Kazemi, Kourosh

    2016-06-01

    Polymorphisms of the endothelial nitric oxide synthase gene have been associated with altered endothelial nitric oxide synthase activity. The purpose of this study was to investigate the relation between endothelial nitric oxide synthase -786T/C and 894G/T polymorphism and their haplotypes on the occurrence of acute rejection episodes in liver transplant recipients. We conducted a case control study in which 100 liver transplant recipients and 100 healthy controls were recruited from Shiraz Transplant Center. The patients used triple therapy including tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression maintenance. DNA was extracted from peripheral blood and endothelial nitric oxide synthase polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. Patients included 60 men and 40 women (mean age, 32.35 ± 10.2 y). There was a significant association of endothelial nitric oxide synthase 894G/T and acute rejection episode. The GT* gen-otype and acute rejection episodes had a significant association (odds ratio, 2.42; 95% confidence interval, 0.97-6.15; P = .03). The GG and GT* genotype and T* allele frequency were significantly different between patients and control subjects (P = .001). Haplotype TT* was higher in recipients than control subjects (odds ratio, 2.17; 95% confidence interval, 1.12-4.25; P = .01). Haplotype TG was higher in the control group (odds ratio, 0.62; 95% confidence interval, 0.40-0.96; P = .02). Our results suggest a relation between different endothelial nitric oxide synthase geno-types and risk of acute rejection episodes. However, further study is necessary to determine genetic susceptibility for transplant patients.

  15. The liver taxis of receptor mediated lactosaminated human growth hormone

    International Nuclear Information System (INIS)

    Chen Zelian; Shi Lin; Li Tongling; Pang Qijie; He Juying; Guan Changtian

    2002-01-01

    Radiography imaging is used to assess liver taxis mechanism of anti-dwarfism drug lactosaminated human growth hormone (L-rhGH). Both L-rhGH and rhGH labelled with 131 I are used to study their biodistribution in animals (including rabbits, cocks and rats). The results show that L-rhGH is of specific hepatic targeting property, and the maximum hepatic concentration rate is 76.8%, which is two times of rhGH. Its hepatic binding is receptor mediated

  16. Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience

    Directory of Open Access Journals (Sweden)

    Vernadakis S

    2011-08-01

    Full Text Available Abstract Objective Orthotopic-liver-transplantation (OLT in patients with Human-Immunodeficiency-Virus infection (HIV and end-stage-liver-disease (ESDL is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients. Material and methods This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post-OLT. Results Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61 years were included. OLT indications were HCV (n = 5, HBV (n = 2, HCV/HBV/HDV-related cirrhosis (n = 1 and acute liver-failure (n = 1. At OLT, CD4 cell-counts ranged from 113-621 cells/μl, and HIV viral-loads from Conclusions OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease-progression under antiretroviral therapy and management of the viral hepatitis co-infection.

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

    Science.gov (United States)

    Anastasiou, Olympia; Sydor, Svenja; Sowa, Jan-Peter; Manka, Paul; Katsounas, Antonios; Syn, Wing-Kin; Führer, Dagmar; Gieseler, Robert K; Bechmann, Lars P; Gerken, Guido; Moeller, Lars C; Canbay, Ali

    2015-01-01

    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.

  18. MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

    International Nuclear Information System (INIS)

    Uematsu, Yasuaki; Akai, Sho; Tochitani, Tomoaki; Oda, Shingo; Yamada, Toru; Yokoi, Tsuyoshi

    2016-01-01

    MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

  19. MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Uematsu, Yasuaki, E-mail: yasuaki-uematsu@ds-pharma.co.jp [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Akai, Sho [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Tochitani, Tomoaki [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Oda, Shingo [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Yamada, Toru [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Yokoi, Tsuyoshi [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2016-09-15

    MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

  20. miRNA signatures can predict acute liver failure in hepatitis E infected pregnant females

    Directory of Open Access Journals (Sweden)

    Nirupma Trehanpati

    2017-04-01

    Full Text Available Background: Acute viral hepatitis E (AVH-E can often result in acute liver failure (ALF during pregnancy. microRNAs serve as mediators in drug induced liver failure. We investigated their role as a biomarker in predicting ALF due to HEV (ALF-E. Methods: We performed next generation sequencing and subsequent validation studies in PBMCs of pregnant (P self limiting AVH-E, ALF due to HEV (ALF-E and compared with AVH-E in non-pregnant (NP females and healthy controls. Findings: Eleven microRNAs were significantly expressed in response to HEV infection; importantly, miR- 431, 654, 1468 and 4435, were distinctly expressed in pregnant self-limiting AVH-E and healthy females (p = 0.0005, but not in ALF-E. Sixteen exclusive microRNAs differentiated ALF-E from self limiting AVH-E in pregnant females. miR-450b which affects cellular proliferation and metabolic processes through RNF20 and SECB was predominanlty upregulated and correlated with poor outcome (ROC 0.958, p = 0.001. Interpretation: Our results reveal that a specific microRNA profile can predict fatality in ALF-E in pregnancy. These microRNAs could be exploited as prognostic biomarkers and help in the development of new therapeutic interventions. Keywords: Health sciences, Virology

  1. Protective effect of Sida cordata leaf extract against CCl(4) induced acute liver toxicity in rats.

    Science.gov (United States)

    Mistry, Sunil; Dutt, K R; Jena, J

    2013-04-13

    To investigate the hepatoprotective potential of Sida cordata (Malvaceae) (S. cordata) in experimental rats to validate its traditional claim. Wister albino rats were divided into 6 groups: Group I served as control; Group II served as hepatotoxic (CCl(4) treated) group; Group III, IV and V served as (100, 200 and 400 mg/kg b.w.) S. cordata leaf extract (SCLE) treated groups; Group VI served as positive control (Silymarin) treated group. Liver marker enzymes serum glutamate oxyloacetic transaminase, serum glutamic pyruvic transaminase, pancreatic enzymatic antioxidants superoxide dismutase (SOD), lipid peroxidation, catalase (CAT), reduced glutathione (GSH) were measured and compared along with histopathological studies. Obtained results show that the treatment with SCLE significantly (P<0.05-<0.001) and dose-dependently reduced CCl4 induced elevated serum level of hepatic enzymes. Furthermore, SCLE significantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels, which was confirmed by the histopathological studies. The results of this study strongly indicate the protective effect of SCLE against CCl(4) induced acute liver toxicity in rats and thereby scientifically support its traditional use. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  2. Effect of intraperitoneal selenium administration on liver glycogen levels in rats subjected to acute forced swimming.

    Science.gov (United States)

    Akil, Mustafa; Bicer, Mursel; Kilic, Mehmet; Avunduk, Mustafa Cihat; Mogulkoc, Rasim; Baltaci, Abdulkerim Kasim

    2011-03-01

    There are a few of studies examining how selenium, which is known to reduce oxidative damage in exercise, influences glucose metabolism and exhaustion in physical activity. The present study aims to examine how selenium administration affects liver glycogen levels in rats subjected to acute swimming exercise. The study included 32 Sprague-Dawley type male rats, which were equally allocated to four groups: Group 1, general control; Group 2; selenium-supplemented control (6 mg/kg/day sodium selenite); Group 3, swimming control; Group 4, selenium-supplemented swimming (6 mg/kg/day sodium selenite). Liver tissue samples collected from the animals at the end of the study were fixed in 95% ethyl alcohol. From the tissue samples buried into paraffin, 5-µm cross-sections were obtained using a microtome, put on a microscope slide, and stained with PAS. Stained preparations were assessed using a Nikon Eclipse E400 light microscope. All images obtained with the light microscope were transferred to a PC and evaluated using Clemex PE 3.5 image analysis software. The highest liver glycogen levels were found in groups 1 and 2 (p swimming exercise can be restored by selenium administration. It can be argued that physiological doses of selenium administration can contribute to performance.

  3. Acute Sickle Hepatic Crisis after Liver Transplantation in a Patient with Hb SC Disease

    Directory of Open Access Journals (Sweden)

    J. H. Gillis

    2015-01-01

    Full Text Available Acute sickle hepatic crisis (ASHC has been observed in approximately 10% of patients with sickle cell disease. It occurs predominantly in patients with homozygous (Hb SS sickle cell anemia and to a lesser degree in patients with Hb SC disease, sickle cell trait, and Hb S beta thalassemia. Patients commonly present with jaundice, right upper quadrant pain, nausea, low-grade fever, tender hepatomegaly, and mild to moderate elevations in serum AST, ALT, and bilirubin. We describe the case of a patient with a history of hemoglobin SC disease and cirrhosis caused by hepatitis C presenting approximately 1 year after liver transplantation with an ASHC. The diagnosis was confirmed by liver biopsy. Our patient was treated with RBC exchange transfusions, IV hydration, and analgesia and made a complete recovery. Only a limited number of patients with sickle cell disease have received liver transplants, and, to our knowledge, this is the first case of ASHC after transplantation in a patient with Hb SC disease.

  4. Validation of prognostic scores to predict short-term mortality in patients with acute-on-chronic liver failure.

    Science.gov (United States)

    Song, Do Seon; Kim, Tae Yeob; Kim, Dong Joon; 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; Choe, Won Hyeok; Yim, Hyung Joon; Kim, Sung Eun; Baik, Soon Koo; Jang, Jae Young; Kim, Hyoung Su; Kim, Sang Gyune; Yang, Jin Mo; Sohn, Joo Hyun; Choi, Eun Hee; Cho, Hyun Chin; Jeong, Soung Won; Kim, Moon Young

    2018-04-01

    The aim of this study was to validate the chronic liver failure-sequential organ failure assessment score (CLIF-SOFAs), CLIF consortium organ failure score (CLIF-C OFs), CLIF-C acute-on-chronic liver failure score (CLIF-C ACLFs), and CLIF-C acute decompensation score in Korean chronic liver disease patients with acute deterioration. Acute-on-chronic liver failure was defined by either the Asian Pacific Association for the study of the Liver ACLF Research Consortium (AARC) or CLIF-C criteria. The diagnostic performances for short-term mortality were compared by the area under the receiver operating characteristic curve. Among a total of 1470 patients, 252 patients were diagnosed with ACLF according to the CLIF-C (197 patients) or AARC definition (95 patients). As the ACLF grades increased, the survival rates became significantly lower. The areas under the receiver operating characteristic of the CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs were significantly higher than those of the Child-Pugh, model for end-stage liver disease, and model for end-stage liver disease-Na scores in ACLF patients according to the CLIF-C definition (all P < 0.05), but there were no significant differences in patients without ACLF or in patients with ACLF according to the AARC definition. The CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs had higher specificities with a fixed sensitivity than liver specific scores in ACLF patients according to the CLIF-C definition, but not in ACLF patients according to the AARC definition. The CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs are useful scoring systems that provide accurate information on prognosis in patients with ACLF according to the CLIF-C definition, but not the AARC definition. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  5. Quantification of human hepatic binding protein (HBP) via sup 99m Tc-galactosyl-neoglycoalbumin (NGA) liver scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Virgolini, I; Hoebart, J; Bergmann, H; Sinzinger, H [Vienna Univ. (Austria). Abt. fuer Nuklearmedizin; Mueller, C [Vienna Univ. (Austria). 2. Klinik fuer Gastroenterologie und Hepatologie; Angelberger, P [Oesterreichisches Forschungszentrum Seibersdorf GmbH (Austria). Inst. fuer Chemie

    1991-01-01

    {sup 99m}Tc-galactosyl-neoglycoalbumin ({sup 99m}Tc-NGA) was synthesized by covalent coupling of 2-imino-2-methoxyethyl-1-thio-{beta}-D-galactopyranoside to the primary amino groups of human serum albumin. Injections of {sup 99m}Tc-NGA (150 MBq; 3.5 mg (=50 nmol)/ml) demonstrated the liver to be the exclusive site of tracer-uptake. Simulation of {sup 99m}Tc-NGA-kinetics allowed quantification of binding to the hepatic binding protein (HBP). Using this model we studied 250 patients with various liver disease. In alcoholic liver cirrhosis such patients with Child B and Child C stage cirrhosis had a lower HBP-concentration in the liver compared to control individuals. The group with the most advanced cirrhosis had a significantly lower HBP-concentration (0.20-0.45 {mu}mol/l) than Child A patients (0.60-0.85 {mu}mol/l; p<0.01) and Child B patients (0.45-0.60 {mu}mol/l; p<0.05). In patients with biopsy proven liver fibrosis (0.80-1.22 {mu}mol/l) no difference in receptor concentration to normal individuals was estimated. Patients with recently diagnosed acute viral hepatitis underwent repeated {sup 99m}Tc-galactosyl-neoglycoalbumin (NGA) scanning of the liver during the course of the disease. Return of liver function tests to normal values was associated with an increased hepatic imaging size as well as increase in HBP-concentration. In patients exhibiting a prolonged course of the disease changes in NGA-kinetic data were borderline and the hepatic image size unchanged. The values obtained for HBP-concentration in the liver amounted to 0.30-0.50 {mu}mol/l liver for patients with hepatoma, to 0.40-0.60 {mu}mol/l in patients with liver metastasis and to 0.90-1.20 {mu}mol/l in cancer patients without liver malignancy. It is concluded that scintigraphic evaluation of functional hepatic cell mass using the new receptor-tracer {sup 99m}Tc-NGA provides an in vivo diagnostic mean allowing quantitative data on liver function beside assessment of liver morphology.

  6. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, Erwin; Visser, Dorien; Kuipers, Folkert; Blokzijl, Hans; Leuvenink, Henri G. D.; de Jong, Koert P.; Peeters, Paul M. J. G.; Jansen, Peter L. M.; Slooff, Maarten J. H.; Gouw, Annette S. H.; Porte, Robert J.

    2004-01-01

    BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily

  7. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, E; Visser, D; Kuipers, F; Blokzijl, H; Leuvenink, HGD; de Jong, KP; Peeters, PMJG; Jansen, PLM; Slooff, MJH; Gouw, ASH; Porte, RJ

    2004-01-01

    Background/Aims: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. Methods: In 28 liver transplant recipients, bile samples were collected daily

  8. Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.

    Science.gov (United States)

    Gehrke, Nadine; Nagel, Michael; Straub, Beate K; Wörns, Marcus A; Schuchmann, Marcus; Galle, Peter R; Schattenberg, Jörn M

    2018-03-01

    Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP -/- ) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68 + macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP -/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP -/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological

  9. Seasonality in acute liver injury? Findings in two health care claims databases

    Directory of Open Access Journals (Sweden)

    Weinstein RB

    2016-03-01

    Full Text Available Rachel B Weinstein, Martijn J Schuemie, Patrick B Ryan, Paul E Stang Epidemiology, Janssen Research and Development, LLC, Titusville, NJ, USA Background: Presumed seasonal use of acetaminophen-containing products for relief of cold/influenza (“flu” symptoms suggests that there might also be a corresponding seasonal pattern for acute liver injury (ALI, a known clinical consequence of acetaminophen overdose. Objective: The objective of this study was to determine whether there were any temporal patterns in hospitalizations for ALI that would correspond to assumed acetaminophen use in cold/flu season. Methods: In the period 2002–2010, monthly hospitalization rates for ALI using a variety of case definitions were calculated. Data sources included Truven MarketScan® Commercial Claims and Encounters (CCAE and Medicare Supplemental and Coordination of Benefits (MDCR databases. We performed a statistical test for seasonality of diagnoses using the periodic generalized linear model. To validate that the test can distinguish seasonal from nonseasonal patterns, we included two positive controls (ie, diagnoses of the common cold [acute nasopharyngitis] and influenza, believed to change with seasons, and two negative controls (female breast cancer and diabetes, believed to be insensitive to season. Results: A seasonal pattern was observed in monthly rates for common cold and influenza diagnoses, but this pattern was not observed for monthly rates of ALI, with or without comorbidities (cirrhosis or hepatitis, breast cancer, or diabetes. The statistical test for seasonality was significant for positive controls (P<0.001 for each diagnosis in both databases and nonsignificant for ALI and negative controls. Conclusion: No seasonal pattern was observed in the diagnosis of ALI. The positive and negative controls showed the expected patterns, strengthening the validity of the statistical and visual tests used for detecting seasonality. Keywords: acute liver

  10. Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

    Science.gov (United States)

    Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

    2014-06-01

    Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

  11. Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver

    DEFF Research Database (Denmark)

    Vestentoft, Peter S; Jelnes, Peter; Hopkinson, Branden M

    2011-01-01

    BACKGROUND: During liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic...... in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic...

  12. Liver and Muscle Contribute Differently to the Plasma Acylcarnitine Pool During Fasting and Exercise in Humans

    DEFF Research Database (Denmark)

    Xu, G.; Hansen, J S; Zhao, Jian-xin

    2016-01-01

    BACKGROUND: Plasma acylcarnitine levels are elevated by physiological conditions such as fasting and exercise but also in states of insulin resistance and obesity. AIM: To elucidate the contribution of liver and skeletal muscle to plasma acylcarnitines in the fasting state and during exercise...... in humans. METHODS: In 2 independent studies, young healthy males were fasted overnight and performed an acute bout of exercise to investigate either acylcarnitines in skeletal muscle biopsies and arterial-to-venous plasma differences over the exercising and resting leg (n = 9) or the flux over the hepato......-splanchnic bed (n = 10). RESULTS: In the fasting state, a pronounced release of C2- and C3-carnitines from the hepato-splanchnic bed and an uptake of free carnitine by the legs were detected. Exercise further increased the release of C3-carnitine from the hepato-splanchnic bed and the uptake of free carnitine...

  13. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge M.; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, M.T.; Groothuis, Geny M. M.

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict

  14. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  15. Extracellular vesicles from human liver stem cells restore argininosuccinate synthase deficiency.

    Science.gov (United States)

    Herrera Sanchez, Maria Beatriz; Previdi, Sara; Bruno, Stefania; Fonsato, Valentina; Deregibus, Maria Chiara; Kholia, Sharad; Petrillo, Sara; Tolosano, Emanuela; Critelli, Rossana; Spada, Marco; Romagnoli, Renato; Salizzoni, Mauro; Tetta, Ciro; Camussi, Giovanni

    2017-07-27

    Argininosuccinate synthase (ASS)1 is a urea cycle enzyme that catalyzes the conversion of citrulline and aspartate to argininosuccinate. Mutations in the ASS1 gene cause citrullinemia type I, a rare autosomal recessive disorder characterized by neonatal hyperammonemia, elevated citrulline levels, and early neonatal death. Treatment for this disease is currently restricted to liver transplantation; however, due to limited organ availability, substitute therapies are required. Recently, extracellular vesicles (EVs) have been reported to act as intercellular transporters carrying genetic information responsible for cell reprogramming. In previous studies, we isolated a population of stem cell-like cells known as human liver stem cells (HLSCs) from healthy liver tissue. Moreover, EVs derived from HLSCs were reported to exhibit regenerative effects on the liver parenchyma in models of acute liver injury. The aim of this study was to evaluate whether EVs derived from normal HLSCs restored ASS1 enzymatic activity and urea production in hepatocytes differentiated from HLSCs derived from a patient with type I citrullinemia. HLSCs were isolated from the liver of a patient with type I citrullinemia (ASS1-HLSCs) and characterized by fluorescence-activated cell sorting (FACS), immunofluorescence, and DNA sequencing analysis. Furthermore, their differentiation capabilities in vitro were also assessed. Hepatocytes differentiated from ASS1-HLSCs were evaluated by the production of urea and ASS enzymatic activity. EVs derived from normal HLSCs were purified by differential ultracentrifugation followed by floating density gradient. The EV content was analyzed to identify the presence of ASS1 protein, mRNA, and ASS1 gene. In order to obtain ASS1-depleted EVs, a knockdown of the ASS1 gene in HLSCs was performed followed by EV isolation from these cells. Treating ASS1-HLSCs with EVs from HLSCs restored both ASS1 activity and urea production mainly through the transfer of ASS1 enzyme

  16. Acute liver failure caused by hepatitis E virus genotype 3 and 4: A systematic review and pooled analysis.

    Science.gov (United States)

    Haffar, Samir; Shalimar; Kaur, Ravinder J; Wang, Zhen; Prokop, Larry J; Murad, Mohammad H; Bazerbachi, Fateh

    2018-04-19

    Acute liver failure caused by hepatitis E virus genotype 3 and 4 has been rarely described. Because of the presence of a short golden therapeutic window in patients with viral acute liver failure from other causes, it is possible that early recognition and treatment might reduce the morbidity and mortality. We performed a systematic review and pooled analysis of acute liver failure caused by hepatitis E virus genotype 3 and 4. Two reviewers appraised studies after searching multiple databases on June 12th, 2017. Appropriate tests were used to compare hepatitis E virus genotype 3 vs 4, suspected vs confirmed genotypes, hepatitis E virus-RNA positive vs negative, and to discern important mortality risk factors. We identified 65 patients, with median age 58 years (range: 3-79), and a male to female ratio of 1.2:1. The median bilirubin, ALT, AST and alkaline phosphatase (expressed by multiplication of the upper limit of normal) levels were 14.8, 45.3, 34.8 and 1.63 respectively. Antihepatitis E virus IgG, antihepatitis E virus IgM and hepatitis E virus-RNA were positive in 84%, 91% and 86% of patients respectively. The median interval from symptoms onset to acute liver failure was 23 days, and 16 patients underwent liver transplantation. Final outcome was reported in 58 patients and mortality was 46%. Age was a predictor of poor prognosis in multivariate analysis. No important differences were found between patients infected with genotype 3 vs 4, patients with confirmed vs suspected genotypes, or patients with positive vs negative RNA. Acute liver failure caused by hepatitis E virus genotype 3 and 4 is rare, similar between genotypes, occurs commonly in middle-aged/elderly patients and has a very high mortality. Age is predictive of poor prognosis in multivariate analysis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Effects of grape seed polyphenols on oxidative damage in liver tissue of acutely and chronically exercised rats.

    Science.gov (United States)

    Belviranlı, Muaz; Gökbel, Hakkı; Okudan, Nilsel; Büyükbaş, Sadık

    2013-05-01

    The objective of the present study was to investigate the effects of grape seed extract (GSE) supplementation on oxidative stress and antioxidant defense markers in liver tissue of acutely and chronically exercised rats. Rats were randomly assigned to six groups: Control (C), Control Chronic Exercise (CE), Control Acute Exercise (AE), GSE-supplemented Control (GC), GSE-supplemented Chronic Exercise(GCE) and GSE-supplemented Acute Exercise (GAE). Rats in the chronic exercise groups were subjected to a six-week treadmill running and in the acute exercise groups performed an exhaustive running. Rats in the GSE supplemented groups received GSE (100 mg.kg(-1) .day(-1) ) in drinking water for 6 weeks. Liver tissues of the rats were taken for the analysis of malondialdehyde (MDA), nitric oxide (NO) levels and total antioxidant activity (AOA) and xanthine oxidase (XO) activities. MDA levels decreased with GSE supplementation in control groups but increased in acute and chronic exercise groups compared to their non-supplemented control. NO levels increased with GSE supplementation. XO activities were higher in AE group compared to the CE group. AOA decreased with GSE supplementation. In conclusion, while acute exercise triggers oxidative stress, chronic exercise has protective role against oxidative stress. GSE has a limited antioxidant effect on exercise-induced oxidative stress in liver tissue.

  18. Analysis of images of acute human and animal leukaemia

    International Nuclear Information System (INIS)

    Feinermann, Emmanuel

    1981-01-01

    This research thesis first proposes a review of the development of stereology: historical backgrounds, basic principles. It discusses the choices regarding instrumentation: Coulter counter (principle and theory), quantitative analysis of particles, image analyser (optical microscope, epidiascope, scanners, detection, electronic pencil, computers, programming and data processing system), and stereo-logical parameters. The author then reports the stereo-logical study of acute human leukaemia: definition, classification, determination of spherical particle size distribution, lympho-blast size distributions. He reports the comparative study of rat L 5222 leukaemia and Brown Norway rat acute myelocytic leukaemia, and discusses their relationship with acute human leukaemia

  19. Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

    Science.gov (United States)

    Unzu, C; Melero, I; Hervás-Stubbs, S; Sampedro, A; Mancheño, U; Morales-Kastresana, A; Serrano-Mendioroz, I; de Salamanca, R E; Benito, A; Fontanellas, A

    2015-11-01

    Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.

  20. Endovascular treatment of acute arterial complications after living-donor liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, G.S. [Department of Diagnostic Radiology, Ajou University Hospital, School of Medicine, San 5, Wonchun-dong, Youngtong-gu, Suwon, Gyeonggido 443-721 (Korea, Republic of); Won, J.H. [Department of Diagnostic Radiology, Ajou University Hospital, School of Medicine, San 5, Wonchun-dong, Youngtong-gu, Suwon, Gyeonggido 443-721 (Korea, Republic of)], E-mail: wonkwak@ajou.ac.kr; Wang, H.J.; Kim, B.W. [Department of Surgery, Ajou University Hospital, School of Medicine, San 5, Wonchun-dong, Youngtong-gu, Suwon, Gyeonggido 443-721 (Korea, Republic of); Lee, B.M. [Department of Surgery, Aerospace medical center, Ssangsu-ri, Cheongwon-gun, Chungcheongbuk-do 363-849 (Korea, Republic of)

    2008-10-15

    Aim: The aim of this study was to evaluate the efficacy of endovascular treatment for acute arterial complications following living-donor liver transplantation (LDLT). Materials and methods: Of 79 LDLT patients, 17 (mean age 48 {+-} 8 years, range 33-66 years) who had acute arterial complications and underwent endovascular treatment were evaluated. Transcatheter arterial embolization was performed to control peritoneal bleeding. Catheter-directed thrombolysis using urokinase was performed in hepatic artery thromboses. The locations of complications and materials used were evaluated. The technical and clinical success rates were calculated. Results: Twenty-three acute arterial complications, including four hepatic artery thromboses and 19 cases of peritoneal haemorrhages were identified in 22 angiographic sessions in 17 patients. The mean duration between LDLT and first angiography was 3.2 {+-} 3.5 days (range 1-13 days). Hepatic artery recanalization with catheter-directed thrombolysis using urokinase was achieved in two patients. Transcatheter arterial embolization for peritoneal bleeding was successfully performed in 16 cases. The most common bleeding focus was the right inferior phrenic artery. Additional surgical management was needed in five patients to control bleeding or hepatic artery recanalization. Technical and clinical success rates of transcatheter arterial embolization were 84.2 and 63.1%, respectively. Overall technical success was achieved in 18 of 23 arterial complications (78.2%), and clinical success was achieved in 14 of 23 arterial complications (60.8%). Conclusion: Endovascular treatment for the acute arterial complications of haemorrhage or thrombosis in LDLT patients is safe and effective. Therefore, it should be considered as the first line of treatment in selective cases.

  1. Stevia Prevents Acute and Chronic Liver Injury Induced by Carbon Tetrachloride by Blocking Oxidative Stress through Nrf2 Upregulation

    Science.gov (United States)

    Ramos-Tovar, Erika; Hernández-Aquino, Erika; Casas-Grajales, Sael; Buendia-Montaño, Laura D.; Tsutsumi, Víctor

    2018-01-01

    The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl4-) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cholestasis, which were significantly ameliorated by stevia. Chronic CCl4 treatment resulted in liver cirrhosis, as evidenced by nodules of hepatocytes surrounded by thick bands of collagen and distortion of the hepatic architecture, and stevia significantly prevented these alterations. Subsequently, the underlying mechanism of action of the plant was analyzed. Our study for the first time shows that stevia upregulated Nrf2, thereby counteracting oxidative stress, and prevented necrosis and cholestasis through modulation of the main proinflammatory cytokines via NF-κB inhibition. These multitarget mechanisms led to the prevention of experimental cirrhosis. Given the reasonable safety profile of stevia, our results indicated that it may be useful for the clinical treatment of acute and chronic liver diseases. PMID:29849889

  2. Fetal liver transplantation in 2 patients with acute leukaemia after total body irradiation

    International Nuclear Information System (INIS)

    Lucarelli, G.; Izzi, T.; Porcellini, A.; Delfini, C.; Galimberti, M.; Moretti, L.; Polchi, P.; Agostinelli, F.; Andreani, M.; Manna, M.; Dallapiccola, B.

    1982-01-01

    2 patients with acute leukaemia in relapse were transplanted with fetal liver cells following a conditioning regimen of cyclophosphamide (120 mg/kg) and total body irradiation (1000 r). Each patient achieved a remission with haematopoietic recovery that was rapid in one case and delayed in the other. In one case there was evidence of chimerism as demonstrated by the presence of the XYY karyotype of the donor fetus in 20 % of marrow metaphases, by the presence of double Y bodies in the peripheral blood, by the appearance of new HLA-antigens, and by red cell isoenzyme phenotypes of donor origin. In the second case there was prompt haemotopoietic recovery and the appearance of red cell isoenzyme phenotypes of donor origin. Survival was 153 and 30 d, respectively, and both patients died of interstitial pneumonia without evidence of graft versus host disease. (author)

  3. Effect of the Human Amniotic Membrane on Liver Regeneration in Rats

    Directory of Open Access Journals (Sweden)

    Mesut Sipahi

    2015-01-01

    Full Text Available Introduction. Operations are performed for broader liver surgery indications for a better understanding of hepatic anatomy/physiology and developments in operation technology. Surgery can cure some patients with liver metastasis of some tumors. Nevertheless, postoperative liver failure is the most feared complication causing mortality in patients who have undergone excision of a large liver mass. The human amniotic membrane has regenerative effects. Thus, we investigated the effects of the human amniotic membrane on regeneration of the resected liver. Methods. Twenty female Wistar albino rats were divided into control and experimental groups and underwent a 70% hepatectomy. The human amniotic membrane was placed over the residual liver in the experimental group. Relative liver weight, histopathological features, and biochemical parameters were assessed on postoperative day 3. Results. Total protein and albumin levels were significantly lower in the experimental group than in the control group. No difference in relative liver weight was observed between the groups. Hepatocyte mitotic count was significantly higher in the experimental group than in the control group. Hepatic steatosis was detected in the experimental group. Conclusion. Applying the amniotic membrane to residual liver adversely affected liver regeneration. However, mesenchymal stem cell research has the potential to accelerate liver regeneration investigations.

  4. Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease.

    Science.gov (United States)

    Willebrords, Joost; Maes, Michaël; Pereira, Isabel Veloso Alves; da Silva, Tereza Cristina; Govoni, Veronica Mollica; Lopes, Valéria Veras; Crespo Yanguas, Sara; Shestopalov, Valery I; Nogueira, Marina Sayuri; de Castro, Inar Alves; Farhood, Anwar; Mannaerts, Inge; van Grunsven, Leo; Akakpo, Jephte; Lebofsky, Margitta; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2018-03-01

    Pannexins are transmembrane proteins that form communication channels connecting the cytosol of an individual cell with its extracellular environment. A number of studies have documented the presence of pannexin1 in liver as well as its involvement in inflammatory responses. In this study, it was investigated whether pannexin1 plays a role in acute liver failure and non-alcoholic steatohepatitis, being prototypical acute and chronic liver pathologies, respectively, both featured by liver damage, oxidative stress and inflammation. To this end, wild-type and pannexin1 -/- mice were overdosed with acetaminophen for 1, 6, 24 or 48h or were fed a choline-deficient high-fat diet for 8weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, lipid accumulation, protein adduct formation, oxidative stress and inflammation. In parallel, in order to elucidate molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. The results of this study show that pannexin1 -/- diseased mice present less liver damage and oxidative stress, while inflammation was only decreased in pannexin1 -/- mice in which non-alcoholic steatohepatitis was induced. A multitude of genes related to inflammation, oxidative stress and xenobiotic metabolism were differentially modulated in both liver disease models in wild-type and in pannexin1 -/- mice. Overall, the results of this study suggest that pannexin1 may play a role in the pathogenesis of liver disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Cytokine and acute phase protein gene expression in liver biopsies from dairy cows with a lipopolysaccharide - induced mastitis

    DEFF Research Database (Denmark)

    Vels, J; Røntved, Christine M.; Bjerring, Martin

    2009-01-01

    A minimally invasive liver biopsy technique was tested for its applicability to study the hepatic acute phase response (APR) in dairy cows with Escherichia coli lipopolysaccharide (LPS)-induced mastitis. The hepatic mRNA expression profiles of the inflammatory cytokines, tumor necrosis factor (TNF......, a minimally invasive liver biopsy technique can be used for studying the hepatic APR in diseased cattle. Lipopolysaccharide-induced mastitis resulted in a time-dependent production of inflammatory cytokines and SAA and Hp in the liver of dairy cows.......- ), IL-1β, IL-6, and IL-10, and the acute phase proteins serum amyloid A isoform 3 (SAA3), haptoglobin (Hp), and 1-acid glycoprotein (AGP) were determined by real-time reverse transcription-PCR. Fourteen primiparous cows in mid lactation were challenged with 200 µg of LPS (n = 8) or NaCl solution (n = 6...

  6. Alpha-fetoprotein as a prognostic marker in acute liver failure: a pilot study.

    Science.gov (United States)

    Varshney, Anshul; Gupta, Rohit; Verma, Sanjiv K; Ahmad, Sohaib

    2017-07-01

    Prognostic markers of acute liver failure (ALF) are based on clinical, laboratory or radiological parameters. Most of the biochemical markers are based on hepatic degeneration. We studied the impact of serial serum alpha-fetoprotein (AFP) levels, a marker of liver regeneration, on the outcome of the patients with ALF. AFP levels were estimated on days 1 and 3 of hospitalisation of 32 patients with ALF and the ratio (AFP day3/day1) was calculated. All subjects were categorised as group A (expired) or group B (survived). The AFP ratio was 0.84  +  0.15 in group A (n = 20) versus 1.55  +  0.70 in group B (n = 10); P < 0.001. However, the absolute initial AFP values were not associated with the outcome, favourable or unfavourable. We conclude that AFP levels change dynamically during ALF and have the potential to be used as a predictor of outcome in isolation or in combination with well-established prognostic markers.

  7. "ACUTE FATTY LIVER OF PREGNANCY AND PREECLAMPSIA IN A TRIPLET GESTATION "

    Directory of Open Access Journals (Sweden)

    M. Ghaffarnejad

    2007-06-01

    Full Text Available Acute fatty liver of pregnancy (AFLP is a rare entity and a potentially fatal disorder. It is reported to be more common in multiple than singleton pregnancies. Sometimes it coincides with preeclampsia but the exact etiology is not yet understood. A 31-year-old G2 P1 patient admitted at 33 weeks of pregnancy with signs and symptoms of jaundice, gastroenteritis, hypertension, malaise, urinary incontinence and preterm contractions. She had history of idiopathic hypothalamic amenorrhea and by a recent trial with gonadotropins, she had got triplet gestation. After admission her general condition deteriorated. She underwent Cesarean section at once and all fetuses survived. She had severe postpartum hemorrhage. The results of laboratory tests indicated coagulopathy and liver function abnormalities. The AFLP was diagnosed on the third day of hospital stay. She was discharged one week later. Again she returned with complaint of severe sustained headache. Computed tomography showed subdural hemorrhage and drainage of hematoma was performed immediately. Finally the patient recovered from all of these critical conditions. This is the first report of AFLP in a patient with history of idiopathic hypothalamic amenorrhea. AFLP should be suspected in every pregnant patient with preeclampsia and gastroenteritis symptoms in the third trimester of pregnancy.

  8. Temporal changes in rat liver gene expression after acute cadmium and chromium exposure.

    Directory of Open Access Journals (Sweden)

    Michael S Madejczyk

    Full Text Available U.S. Service Members and civilians are at risk of exposure to a variety of environmental health hazards throughout their normal duty activities and in industrial occupations. Metals are widely used in large quantities in a number of industrial processes and are a common environmental toxicant, which increases the possibility of being exposed at toxic levels. While metal toxicity has been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify candidate biomarkers, rats were exposed via a single intraperitoneal injection to three concentrations of CdCl2 and Na(2Cr(2O(7, with livers harvested at 1, 3, or 7 days after exposure. Cd and Cr accumulated in the liver at 1 day post exposure. Cd levels remained elevated over the length of the experiment, while Cr levels declined. Metal exposures induced ROS, including hydroxyl radical (•OH, resulting in DNA strand breaks and lipid peroxidation. Interestingly, ROS and cellular damage appeared to increase with time post-exposure in both metals, despite declines in Cr levels. Differentially expressed genes were identified via microarray analysis. Both metals perturbed gene expression in pathways related to oxidative stress, metabolism, DNA damage, cell cycle, and inflammatory response. This work provides insight into the temporal effects and mechanistic pathways involved in acute metal intoxication, leading to the identification of candidate biomarkers.

  9. Acute Fatty Liver of Pregnancy: Analysis on the Diagnosis and Treatment of 15 Cases.

    Science.gov (United States)

    Liu, Guoyan; Shang, Xiaobin; Yuan, Bibo; Han, Cha; Wang, Yingmei

    2016-01-01

    To describe our experience with the diagnosis and management of acute fatty liver of pregnancy (AFLP). The medical records of pregnant women with AFLP were reviewed for symptoms, laboratory findings, treatment, and maternal and fetal outcomes during a 10-year period between January 2003 and December 2013. During the study period 15 women had AFLP as their discharge diagnosis. The mean gestational age at onset was 36 ± 1 weeks. Eleven cases were primigravidas, and 2 had multiple gestations. All patients presented with nausea, vomiting, and epigastric distress followed by jaundice in the third trimester of pregnancy. Raised transaminases and serum bilirubin as well as coagulopathy were found in all patients (100%), while hypoglycemia was found in 8 patients (53%). Ultrasound examination showed enhanced echo or fatty liver in 11 patients. Maternal morbidity included hepatic encephalopathy (n = 1), renal failure (n = 3), ascites (n = 6), hypoglycemia (n = 8), postpartum hemorrhage (n = 6), upper gastrointestinal hemorrhage (n = 1), and preeclampsia (n = 1). Emergency cesarean section was performed in 12 cases and supracervical hysterectomy was performed in 1 patient due to postpartum hemorrhage and disseminated intravascular coagulation (DIC); all patients survived. All neonates survived except for 2 fetal death cases before admission. Early diagnosis and prompt progressive management, including early termination of pregnancy and comprehensive supportive care, are crucial for improving the prognoses of both mother and newborn.

  10. Acute Fatty Liver of Pregnancy: A Retrospective Analysis of 56 Cases

    Directory of Open Access Journals (Sweden)

    Yan-Ping Zhang

    2016-01-01

    Results: The initial symptoms varied considerably, with nausea and vomiting (13/56, 23% being the most common. Liver-function indexes were remarkable, including elevated levels of serum alanine aminotransferase (262.16 ± 281.71 U/L, aspartate aminotransferase (260.98 ± 237.91 U/L, lactic dehydrogenase (1011.76 ± 530.34 U/L, and direct bilirubin (85.59 ± 90.02 μmol/L. Coagulation disorders were indicated by abnormal levels of fibrinogen (245.95 ± 186.11 mg/dL, D-dimer (2.46 ± 4.01 mg/L, and fibrin degradation products (43.62 ± 48.71 mg/L. The main maternal complications were hypoproteinemia (75%, coagulopathy (54%, and acute renal failure (39%. Multivariate logistic regression analysis identified prothrombin time (PT; odds ratio [OR] = 1.558, 95% confidence interval [CI] =1.248–1.946, PORCIP= 0.009 as risk factors. The perinatal infant death rate was related to gestational age at delivery (ORCI PORCI PORCI PConclusions: Nausea and vomiting may be the most common symptoms of AFLP. Indexes of liver dysfunction and coagulation disorders should also be considered. PT and INR are risk factors for fatal complications in patients with AFLP, and perinatal mortality is linked to the level of fibrin degradation products. Timely delivery is crucial to controlling the development of AFLP.

  11. OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model.

    Science.gov (United States)

    Zhi, Xiao; Xue, Fei; Chen, Wei; Liang, Chao; Liu, Hao; Ma, Tao; Xia, Xuefeng; Hu, Liqiang; Bai, Xueli; Liang, Tingbo

    2017-09-01

    Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4 + CD25 - T cells into CD4 + CD25 + forkhead box P3 + Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4 + CD25 + T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

  12. Acute psychophysiological stress impairs human associative learning.

    Science.gov (United States)

    Ehlers, M R; Todd, R M

    2017-11-01

    Addiction is increasingly discussed asa disorder of associative learning processes, with both operant and classical conditioning contributing to the development of maladaptive habits. Stress has long been known to promote drug taking and relapse and has further been shown to shift behavior from goal-directed actions towards more habitual ones. However, it remains to be investigated how acute stress may influence simple associative learning processes that occur before a habit can be established. In the present study, healthy young adults were exposed to either acute stress or a control condition half an hour before performing simple classical and operant conditioning tasks. Psychophysiological measures confirmed successful stress induction. Results of the operant conditioning task revealed reduced instrumental responding under delayed acute stress that resembled behavioral responses to lower levels of reward. The classical conditioning experiment revealed successful conditioning in both experimental groups; however, explicit knowledge of conditioning as indicated by stimulus ratings differentiated the stress and control groups. These findings suggest that operant and classical conditioning are differentially influenced by the delayed effects of acute stress with important implications for the understanding of how new habitual behaviors are initially established. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

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

    Directory of Open Access Journals (Sweden)

    Robim M. Rodrigues

    2016-06-01

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

  15. induced acute cytotoxicity in human cervical epithelial carcinoma cells

    African Journals Online (AJOL)

    Molecular basis of arsenite (As +3 )-induced acute cytotoxicity in human cervical epithelial carcinoma cells. ... Libyan Journal of Medicine ... Methods: After performing cytotoxic assays on a human epithelial carcinoma cell line, expression analysis was done by quantitative polymerase chain reaction, western blotting, and ...

  16. Serum 1H-NMR metabolomic fingerprints of acute-on-chronic liver failure in intensive care unit patients with alcoholic cirrhosis.

    Directory of Open Access Journals (Sweden)

    Roland Amathieu

    Full Text Available INTRODUCTION: Acute-on-chronic liver failure is characterized by acute deterioration of liver function in patients with compensated or decompensated, but stable, cirrhosis. However, there is no accurate definition of acute-on-chronic liver failure and physicians often use this term to describe different clinical entities. Metabolomics investigates metabolic changes in biological systems and identifies the biomarkers or metabolic profiles. Our study assessed the metabolomic profile of serum using proton nuclear magnetic resonance ((1H-NMR spectroscopy to identify metabolic changes related to acute-on-chronic liver failure. PATIENTS: Ninety-three patients with compensated or decompensated cirrhosis (CLF group but stable liver function and 30 patients with cirrhosis and hospitalized for the management of an acute event who may be responsible of acute-on-chronic liver failure (ACLF group, were fully analyzed. Blood samples were drawn at admission, and sera were separated and stored at -80°C until (1H-NMR spectral analysis. Using orthogonal projection to latent-structure discriminant analyses, various metabolites contribute to the complete separation between these both groups. RESULTS: The predictability of the model was 0.73 (Q(2 Y and the explained variance was 0.63 (R(2 Y. The main metabolites that had increased signals related to acute-on-chronic liver failure were lactate, pyruvate, ketone bodies, glutamine, phenylalanine, tyrosine, and creatinine. High-density lipids were lower in the ALCF group than in CLF group. CONCLUSION: A serum metabolite fingerprint for acute-on-chronic liver failure, obtained with (1H-NMR, was identified. Metabolomic profiling may aid clinical evaluation of patients with cirrhosis admitted into intensive care units with acute-on-chronic liver failure, and provide new insights into the metabolic processes involved in acute impairment of hepatic function.

  17. Liver slices in in vitro pharmacotoxicology with special reference to the use of human liver tissue

    NARCIS (Netherlands)

    Olinga, Peter; Meijer, D.K F; Slooff, M.JH; Groothuis, Geny

    In the early years of research in in vitro pharmacotoxicology liver slices have been used. After a decline in the application of slices in favour of the use of isolated hepatocytes and the isolated perfused liver preparation, the development of the Krumdieck slicer in the 1980s led to a 'comeback'

  18. Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver.

    Science.gov (United States)

    Kitamura, Shigeyuki; Sugihara, Kazumi

    2014-01-01

    1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

  19. Photosensitivity and Acute Liver Insufficiency in Late-Onset Erythropoietic Protoporphyria with a Chromosome 18q Abnormality

    Directory of Open Access Journals (Sweden)

    Yuka Oshikawa

    2012-07-01

    Full Text Available Late-onset erythropoietic protoporphyria (EPP is rare, and it is usually associated with an acquired somatic mutation of the ferrochelatase gene secondary to hematological malignancy such as myelodysplastic syndrome or myeloproliferative disorder. In 0.5–1% of patients with EPP, deposition of protoporphyrin in the liver leads to progressive liver insufficiency. Herein, we report the case of a 67-year-old female who developed EPP with typical photosensitivity and hemolytic anemia. Six months later, she was admitted with acute liver damage with a rapidly progressing course, and developed liver insufficiency. She recovered from the liver insufficiency after undergoing plasmapheresis and red blood cell exchange transfusion. A bone marrow examination revealed normal features; however, a cytogenetic analysis identified an abnormal clone of cells with a translocation between chromosomes 13q12 and 18q21.1. This is the first report of a patient who recovered from liver insufficiency. The results of this report suggest that plasmapheresis and red blood cell exchange transfusion are effective for treating liver insufficiency in patients with late-onset EPP.

  20. Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure: A Propensity-Score Matched Population-Based Retrospective Cohort Study.

    Science.gov (United States)

    Knight, Stephen R; Oniscu, Gabriel C; Devey, Luke; Simpson, Kenneth J; Wigmore, Stephen J; Harrison, Ewen M

    2016-01-01

    Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy. A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use. Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (Prenal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01-2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy. In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial.

  1. Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice.

    Science.gov (United States)

    Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

    2017-09-11

    Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke ( Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF-κB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported.

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

    Science.gov (United States)

    Yang, Runkuan; Zou, Xiaoping; Tenhunen, Jyrki; Tønnessen, Tor Inge

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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. Hydroalcoholic extract of Stevia rebaudiana bert. leaves and stevioside ameliorates lipopolysaccharide induced acute liver injury in rats.

    Science.gov (United States)

    S, Latha; Chaudhary, Sheetal; R S, Ray

    2017-11-01

    Oxidative stress and hepatic inflammatory response is primarily implicated in the pathogenesis of LPS induced acute liver injury. Stevioside, a diterpenoidal glycoside isolated from the Stevia rebaudiana leaves, exerts potent anti-oxidant, anti-inflammatory and immunomodulatory activities. The present study was aimed to investigate the hepatoprotective effect of hydroalcoholic extract of Stevia rebaudiana leaves (STE EXT) and its major phytochemical constituent, stevioside (STE) in LPS induced acute liver injury. The hepatoprotective activity of STE EXT (500mg/kg p.o) and STE (250mg/kg p.o) was investigated in lipopolysaccharide (LPS 5mg/kg i.p.) induced acute liver injury in male wistar rats. Our results revealed that both STE EXT and STE treatment ameliorated LPS induced hepatic oxidative stress, evident from altered levels of reduced SOD, Catalase, GSH, MDA, NO. Histopathological observations revealed that both STE EXT and STE attenuated LPS induced structural changes and hepatocellular apoptosis providing additional evidence for its hepatoprotective effect. Further, STE EXT and STE significantly restored the elevated serum and tissue levels of AST and ALT in LPS treated rats. Furthermore, both STE EXT and STE rescued hepatocellular dysfunctions to normal by altering the level of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 exhibiting its anti-inflammatory potential. In conclusion, both STE EXT and STE demonstrated excellent hepatoprotective effects against endotoxemia induced acute liver injury possibly through suppression of hepatic inflammatory response and oxidative stress, attributing to its medicinal importance in treating various liver ailments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Acetaminophen (Paracetamol) induced acute liver failure - A social problem in an era of increasing tendency to self-treatment.

    Science.gov (United States)

    Wróblewski, Tadeusz; Kobryń, Konrad; Kozieł, Sławomir; Ołdakowska-Jedynak, Urszula; Pinkas, Jarosław; Danielewicz, Roman; Ziarkiewicz-Wróblewska, Bogna; Krawczyk, Marek

    2015-01-01

    The widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure. In 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx). 26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant. Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  7. mRNA Expression of Interferon Regulatory Factors during Acute Rejection of Liver Transplants in Patients with Autoimmune Hepatitis.

    Science.gov (United States)

    Nasiri, M; Geramizadeh, B; Nabavizadeh, S H; Male-Hosseini, S A; Karimi, M H; Saadat, I

    2018-01-01

    Interferon regulatory factors (IRFs) can play a critical role in the regulation of many facets of innate and adaptive immune responses through transcriptional activation of type I interferons, other proinflammatory cytokines, and chemokines. However, their roles in transplantation immunity still remain to be elucidated. To evaluate the time course of mRNA expression of all 9 members of IRFs family of transcription factors during liver allograft acute rejection. Blood samples of 19 patients with autoimmune hepatitis receiving liver transplants were collected on days 1, 3, 5, and 7 post-transplantation. The patients were followed for 6 months after transplantation and divided into two groups of acute rejection (AR) (n=4) and non-acute rejection (non-AR) (n=15). All of the studied transcription factors were down-regulated in AR-group on days 3, 5, and 7 post-transplantation compared to non-AR group. The mean±SEM IRF5 on day 7 post-transplantation was significantly (p=0.005) lower in AR-group than in non-AR group (0.7±0.21 vs . 1.91±0.27, respectively); expression of other IRFs family members was not significantly different between the two groups on days 3, 5, and 7 post-transplantation. IRF5 may have an important role during the acute rejection of liver transplants.

  8. Acute Liver Failure from Herpes Simplex Virus in an Immunocompetent Patient Due to Direct Inoculation of the Peritoneum.

    Science.gov (United States)

    Chaudhary, Dhruv; Ahmed, Shifat; Liu, Nanlong; Marsano-Obando, Luis

    2017-01-01

    Herpes simplex virus (HSV) hepatitis is a rare cause of acute liver failure (ALF). It carries a mortality rate of 80% if untreated, thus early identification and treatment are critical. Without high clinical suspicion, HSV hepatitis is difficult to diagnose. A 48-year-old Hispanic female presented with a 4-day history of abdominal pain and a vaginal cuff tear requiring laparoscopic repair. She subsequently developed postsurgical disseminated HSV, resulting in ALF. Acyclovir was initiated, but she was resistant to treatment. She was given additional foscarnet and responded without requiring a liver transplant.

  9. Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice

    OpenAIRE

    Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

    2017-01-01

    Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke (Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight)...

  10. Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series

    Directory of Open Access Journals (Sweden)

    Castellote José

    2011-07-01

    Full Text Available Abstract Background Acute liver injury (ALI induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug. The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. Methods Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. Results In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8 and of 10 per million paracetamol users-year (95% CI 4.3-19.4. Conclusions Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

  11. Acute cholestatic liver injury caused by polyhexamethyleneguanidine hydrochloride admixed to ethyl alcohol.

    Science.gov (United States)

    Ostapenko, Y N; Brusin, K M; Zobnin, Y V; Shchupak, A Y; Vishnevetskiy, M K; Sentsov, V G; Novikova, O V; Alekseenko, S A; Lebed'ko, O A; Puchkov, Y B

    2011-07-01

    Polyhexamethyleneguanidine hydrochloride (PHMG) is an antimicrobial biocide of the guanidine family. In the period from August 2006 to May 2007, more than 12500 patients were admitted to hospital with a history of drinking illegal cheap "vodka" in 44 different regions in Russia, of whom 9.4% died. In reality, the "vodka" was an antiseptic liquid composed of ethanol (≈93%), diethyl phthalate, and 0.1-0.14% PHMG (brand name "Extrasept-1"). We performed an analysis of the clinical features and outcome in four poisoning treatment centers in the cities of Perm, Ekaterinburg, Irkutsk, and Khabarovsk. A total of 579 patients (215 females and 364 males) with similar symptoms were included. The main symptoms on admission included jaundice (99.7%), skin itch (78.4%), weakness (96%), anorexia (65.8%), dizziness (65.3%), nausea (54.8%), vomiting (22.6%), stomach ache (52.7%), diarrhea (32%), and fever (50%). Mild symptoms were found in 2.5% of cases, moderate in 63%, and severe in 34.5%. Laboratory results were (mean ± SD): total bilirubin 249 ± 158 μmol/L, direct bilirubin 166 ± 97 μmol/L, cholesterol 14 ± 8 mmol/L, alanine aminotransferase 207 ± 174 IU/L, aspartate aminotransferase 174 ± 230 IU/L, alkaline phosphatase 742 ± 751 IU/L, and gamma-glutamyltranspeptidase 1199 ± 1095 IU/L. Patients generally recovered over a period of 1-5 months, although high levels of alkaline phosphatase and gamma-glutamyltranspeptidase were still found in all patients examined after 6 months. Sixty-one patients (10.5%) died between 23 and 150 days after poisoning. Local cholestasis, inflammatory infiltration, and fibrosis developing into cirrhosis were found by liver biopsy. Acute liver injury caused by PHMG-hydrochloride or PHMG in combination with either ethanol or diethyl phthalate can be characterized as cholestatic hepatitis with a severe inflammatory component causing high mortality.

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

    Science.gov (United States)

    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; Schlienger, R; Reynolds, R; Klungel, O

    2014-10-01

    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. The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.

  13. Acute liver failure in a term neonate after repeated paracetamol administration

    Directory of Open Access Journals (Sweden)

    Fabio Bucaretchi

    2014-03-01

    Full Text Available Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L, hypoglycemia (18mg/dL, increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL after receiving oral paracetamol (10mg/kg/dose every 4 hours for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL. Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.

  14. Improved clinicopathologic assessments of acute liver damage due to trauma in Indian ring-necked parakeets (Psittacula krameri manillensis).

    Science.gov (United States)

    Williams, Susan M; Holthaus, Lisa; Barron, Heather Wilson; Divers, Stephen J; McBride, Michael; Almy, Frederic; Bush, Sharon; Latimer, Kenneth S

    2012-06-01

    Increased activities of certain biochemical enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], alkaline phosphatase [ALP]) have been associated with blunt liver injury in many species. To evaluate changes in plasma hepatic biochemical parameters in acute avian liver disease caused by trauma and to compare biochemical changes with histologic lesions in hepatic parenchyma, 30 healthy fasted Indian ring-necked parakeets (Psittacula krameri manillensis) were divided into 2 groups, and traumatic liver injury was caused by endoscopic liver biopsy (group 1) or by liver biopsy and crushing injury to the hepatic parenchyma with endoscopic forceps (group 2) in anesthetized birds. Blood samples were collected at baseline and at 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours in alternate groups to compare analyte values after injury with those at baseline. Results showed consistently decreased plasma ALP activity (excluding 1 time point) throughout the study, which was thought to be associated with isoflurane administration. Plasma glutamate dehydrogenase activity initially increased but rapidly declined thereafter and was attributed to acute focal hepatocellular injury. In both groups, increases in plasma AST, ALT, and LDH activities was most likely caused by muscle injury because creatine kinase activity was concurrently increased. Compared with baseline values, bile acid concentration and y-glutamyl transferase activity were not affected by liver biopsy or crush injury. Plasma sorbitol dehydrogenase activity was the most specific indicator of liver injury in both groups. Histologic changes correlated poorly with biochemical results, possibly because the small area of hepatic parenchyma that was damaged did not affect enzyme values substantially.

  15. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    International Nuclear Information System (INIS)

    Cheshchevik, V.T.; Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V.; Reiter, R.J.; Prokopchik, N.I.; Zavodnik, I.B.

    2012-01-01

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p 4 displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl 4 , reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage. Highlights: ► After 30-day chronic CCl 4 intoxication mitochondria displayed considerable changes. ► The functional parameters of mitochondria were similar to the control values. ► Melatonin + succinate + flavonoids prevented mitochondrial ultrastructure damage. ► The above complex enhanced regenerative processes in the liver.

  16. Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish

    Directory of Open Access Journals (Sweden)

    Changwen Zhang

    2016-11-01

    Full Text Available Alcoholic liver disease (ALD results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the

  17. Liver lipase and high-density lipoprotein. Lipoprotein changes after incubation of human serum with rat liver lipase.

    Science.gov (United States)

    Groot, P H; Scheek, L M; Jansen, H

    1983-05-16

    Human sera were incubated with rat liver lipase after inactivation of lecithin:cholesterol acyltransferase, and the changes in serum lipoprotein composition were measured. In the presence of liver lipase serum triacylglycerol and phosphatidylcholine were hydrolyzed. The main changes in the concentrations of these lipids were found in the high-density lipoprotein fraction. Subfractionation of high-density lipoprotein by rate-zonal ultracentrifugation showed a prominent decrease in all constituents of high-density lipoprotein2, a smaller decrease in the 'light' high-density lipoprotein3 and an increase in the 'heavy' high-density lipoprotein3. These data support a concept in which liver lipase is involved in high-density lipoprotein2 phospholipid and triacylglycerol catabolism and suggest that as a result of this action high-density lipoprotein2 is converted into high-density lipoprotein3.

  18. Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model.

    Science.gov (United States)

    Rigo, Federica; De Stefano, Nicola; Navarro-Tableros, Victor; David, Ezio; Rizza, Giorgia; Catalano, Giorgia; Gilbo, Nicholas; Maione, Francesca; Gonella, Federica; Roggio, Dorotea; Martini, Silvia; Patrono, Damiano; Salizzoni, Mauro; Camussi, Giovanni; Romagnoli, Renato

    2018-05-01

    The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-α, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-α (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP.

  19. A rapid and simple method for cryopreservation of human liver slices

    NARCIS (Netherlands)

    de Kanter, R; Olinga, Peter; Hof, I.H; de Jager, M.H; Verwillegen, W.A; Slooff, M.JH; Meijer, D.K F; Groothuis, Geny; Koster, H

    1. Precision-cut liver slices represent a suitable and convenient in vitro preparation for studying metabolism and toxicity mechanisms of drugs and toxic chemicals. Particularly in the case of human liver slices, cryopreservation would enable more efficient utilization of this scarce and irregularly

  20. Cell sources for in vitro human liver cell culture models

    Science.gov (United States)

    Freyer, Nora; Damm, Georg; Seehofer, Daniel; Knöspel, Fanny

    2016-01-01

    In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described. PMID:27385595

  1. Metabolism of styrene in the human liver in vitro: interindividual variation and enantioselectivity

    NARCIS (Netherlands)

    Wenker, M. A.; Kezić, S.; Monster, A. C.; de Wolff, F. A.

    2001-01-01

    1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two

  2. Low Platelet to White Blood Cell Ratio Indicates Poor Prognosis for Acute-On-Chronic Liver Failure.

    Science.gov (United States)

    Jie, Yusheng; Gong, Jiao; Xiao, Cuicui; Zhu, Shuguang; Zhou, Wenying; Luo, Juan; Chong, Yutian; Hu, Bo

    2018-01-01

    Background. Platelet to white blood cell ratio (PWR) was an independent prognostic predictor for outcomes in some diseases. However, the prognostic role of PWR is still unclear in patients with hepatitis B related acute-on-chronic liver failure (ACLF). In this study, we evaluated the clinical performances of PWR in predicting prognosis in HBV-related ACLF. Methods. A total of 530 subjects were recruited, including 97 healthy controls and 433 with HBV-related ACLF. Liver function, prothrombin time activity (PTA), international normalized ratio (INR), HBV DNA measurement, and routine hematological testing were performed at admission. Results . At baseline, PWR in patients with HBV-related ACLF (14.03 ± 7.17) was significantly decreased compared to those in healthy controls (39.16 ± 9.80). Reduced PWR values were clinically associated with the severity of liver disease and the increased mortality rate. Furthermore, PWR may be an inexpensive, easily accessible, and significant independent prognostic index for mortality on multivariate analysis (HR = 0.660, 95% CI: 0.438-0.996, p = 0.048) as well as model for end-stage liver disease (MELD) score. Conclusions . The PWR values were markedly decreased in ACLF patients compared with healthy controls and associated with severe liver disease. Moreover, PWR was an independent prognostic indicator for the mortality rate in patients with ACLF. This investigation highlights that PWR comprised a useful biomarker for prediction of liver severity.

  3. Characterization of acute-on-chronic liver failure and prediction of mortality in Asian patients with active alcoholism.

    Science.gov (United States)

    Kim, Hwi Young; Chang, Young; Park, Jae Yong; Ahn, Hongkeun; Cho, Hyeki; Han, Seung Jun; Oh, Sohee; Kim, Donghee; Jung, Yong Jin; Kim, Byeong Gwan; Lee, Kook Lae; Kim, Won

    2016-02-01

    Alcoholic liver diseases often evolve to acute-on-chronic liver failure (ACLF), which increases the risk of (multi-)organ failure and death. We investigated the development and characteristics of alcohol-related ACLF and evaluated prognostic scores for prediction of mortality in Asian patients with active alcoholism. A total of 205 patients who were hospitalized with severe alcoholic liver disease were included in this retrospective cohort study, after excluding those with serious cardiovascular diseases, malignancy, or co-existing viral hepatitis. The Chronic Liver Failure (CLIF) Consortium Organ Failure score was used in the diagnosis and grading of ACLF, and the CLIF Consortium ACLF score (CLIF-C ACLFs) was used to predict mortality. Patients with ACLF had higher Maddrey discriminant function, model for end-stage liver disease (MELD), and MELD-sodium scores than those without ACLF. Infections were more frequently documented in patients with ACLF (33.3% vs 53.0%; P = 0.004). Predictive factors for ACLF development were systemic inflammatory response syndrome (odds ratio [OR], 2.239; P alcohol-related ACLF in Asian patients with active alcoholism. The CLIF-C ACLFs may be more useful for predicting mortality in ACLF cases than liver-specific scoring systems. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  4. Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

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    Michał Szpinda

    2015-01-01

    Full Text Available Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age. The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r=0.91, p<0.001 between the liver volumes achieved by hydrostatic (x and indirect (y methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias.

  5. Long-term culture of human liver tissue with advanced hepatic functions.

    Science.gov (United States)

    Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

    2017-06-02

    A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

  6. Liver transplantation for acute liver failure: a 5 years experience Transplante hepático na hepatite fulminante: uma experiência de 5 anos

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    Cyntia Ferreira Gomes Viana

    2008-09-01

    Full Text Available BACKGROUND: Fulminant hepatic failure carries a high morbidity and mortality. Liver transplantation has markedly improved the prognosis of patients with fulminant hepatic failure. AIM: To evaluate the outcome of 20 patients with acute liver failure and indication for liver transplantation. METHODS: A retrospective review of 20 patients with acute liver failure and indication for liver transplantation was performed. Patients were divided into two groups: group A with 12 patients who underwent liver transplantation and group B with 8 patients who did not receive liver transplantation. Both groups were analyzed according to age, sex, ABO blood type, etiology of acute liver failure, time on list until transplantation or death, and survival rates. Group A patients were additionally analyzed according to preoperative INR, AST, and ALT peak values and MELD (Model for End-stage Liver Disease scores; intraoperative red blood cells and plasma transfusion and cold ischemia time; postoperative lenght of intensive care unit and hospital stay, and needed for dialysis. RESULTS: Group A: there were four men and eight women with an average age of 24.6 years. The average liver waiting time period was 3.4 days and MELD score 36. Seven patients are alive with good hepatic function at a medium follow-up of 26.2 months. The actuarial survival rate was 65.2% at 1 year. Group B: There were two men and six women with an average age of 30.9 years. The mean waiting time on list until death was 7.4 days. All patients died while waiting for a liver donor. CONCLUSION: Despite the improvements in intensive care management, most patients with acute liver failure and indication for liver transplantation ca not survive long without transplant. Liver transplantation is potentially the only curative modality and has markedly improved the prognosis of those patients.RACIONAL: OBJETIVO: Avaliar a evolução de 20 pacientes com insuficiência hepática aguda e indicação de

  7. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    Energy Technology Data Exchange (ETDEWEB)

    Cheshchevik, V.T. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Reiter, R.J. [Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229–3900 (United States); Prokopchik, N.I. [Grodno State Medical University, Gorkogo - 80, 230015 Grodno (Belarus); Zavodnik, I.B., E-mail: zavodnik_il@mail.ru [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus)

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  8. Clinical study of fetal liver transplantation in treatment of four cases of accidental or therapeutic acute radiation sickness

    International Nuclear Information System (INIS)

    1989-01-01

    This report summarized the clinical experience of fetal liver transplantation (FLT) in the medical handling of accidental (case 1) or therapeutic (cases 2-4) acute radiation sickness of severe haemopoietic form. In addition to receiving 80 mg/kg of cyclophosphamide, cases 2, 3 and 4 were exposed to total body single irradiation of 5.5, 5.0 and 5.0 Gy, respectively; while case 1 was exposed to whole body irradiation of 5.2 Gy only. The total number of nucleated fetal liver cells transplanted was 2.26-4.1 x 10 8 /kg. Only 2-5% of peripheral blood cells of cases 2, 3 and 4 were found to have allogeneic marker. The author points out that FLT may be beneficial in those cases of accidental irradiation or patients with acute leukemia when there were no HLA-identical bone marrow donors available

  9. Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Hereti, Rosa I.; Alexandropoulou, Katerina N.; Basayannis, Aristidis C.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi, Attiki 151 27 (Greece)

    2003-12-01

    Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin-eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of {sup 3}H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis

  10. Hops (Humulus lupulus) Content in Beer Modulates Effects of Beer on the Liver After Acute Ingestion in Female Mice.

    Science.gov (United States)

    Landmann, Marianne; Sellmann, Cathrin; Engstler, Anna Janina; Ziegenhardt, Doreen; Jung, Finn; Brombach, Christine; Bergheim, Ina

    2017-01-01

    Using a binge-drinking mouse model, we aimed to determine whether hops (Humulus lupulus) in beer is involved in the less damaging effects of acute beer consumption on the liver in comparison with ethanol. Female C57BL/6 J mice were either fed one iso-alcoholic and iso-caloric bolus dose of ethanol, beer, beer without hops (6 g ethanol/kg body weight) or an iso-caloric bolus of maltodextrin control solution. Markers of steatosis, intestinal barrier function, activation of toll-like receptor 4 signaling cascades, lipid peroxidation and lipogenesis were determined in liver, small intestine and plasma 2 h and 12 h after acute alcohol ingestion. Alcohol-induced hepatic fat accumulation was significantly attenuated in mice fed beer whereas in those fed beer without hops, hepatic fat accumulation was similar to that found in ethanol-fed mice. While markers of intestinal barrier function e.g. portal endotoxin levels and lipogenesis only differed slightly between groups, hepatic concentrations of myeloid differentiation primary response gene 88, inducible nitric oxide synthase (iNOS) and plasminogen-activator inhibitor 1 protein as well as of 4-hydroxynonenal and 3-nitrotyrosine protein adducts were similarly elevated in livers of mice fed ethanol or beer without hops when compared with controls. Induction of these markers was markedly attenuated in mice fed hops-containing beer. Taken together, our data suggest that hops in beer markedly attenuated acute alcohol-induced liver steatosis in female mice through mechanisms involving a suppression of iNOS induction in the liver. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  11. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses

    Directory of Open Access Journals (Sweden)

    Shivendra D. Shukla

    2015-11-01

    Full Text Available Chronic alcoholics who also binge drink (i.e., acute on chronic are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4% for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart. Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9, dually modified phosphoacetylated histone H3 (H3AcK9/PS10, and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10 and H3 ser 28 (H3S28 increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

  12. Acute renal failure, thrombocytopenia, and elevated liver enzymes after concurrent abuse of alcohol and cocaine

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    Alireza Hosseinnezhad

    2011-05-01

    Full Text Available Cocaine has been associated with known adverse effects on cardiac, cerebrovascular and pulmonary systems. However, the effect of cocaine on other organs has not been extensively reported. A middle age man presented with abdominal pain and nausea after inhalation of crack cocaine. On admission, he was found to be hypertensive and tachycardic. Physical examination revealed mild abdominal tenderness without rebound. Laboratory investigations were significant for acute kidney failure with elevated serum creatinine (3.72 mg/dL, thrombocytopenia (platelet count 74,000/UL, elevated alanine and aspartate transaminases (ALT 331 U/L; AST 462 U/L and elevated creatine phosphokinase (CPK 5885 U/L. Urine toxicology screening solely revealed cocaine. A clinical diagnosis of cocaine toxicity was made and patient was admitted to the intensive care unit because of multi organ failure. Despite downward trending of liver enzymes during the hospital course, he continued to have residual renal insufficiency and a low platelet count at the time of discharge. In a patient with history of recent cocaine use presenting with these manifestations, cocaine itself should be considered as a likely cause.

  13. Acute Liver Impairment in a Young, Healthy Athlete: Hypoxic Hepatitis and Rhabdomyolysis following Heat Stroke

    Directory of Open Access Journals (Sweden)

    Neville Azzopardi

    2012-08-01

    Full Text Available Any process that substantially diminishes arterial blood flow or arterial oxygen content to the liver can result in hypoxic (ischaemic hepatitis. 90% of hypoxic hepatitis occurs in unstable patients in intensive care units with haemodynamic failure secondary to heart failure, respiratory failure and toxic shock. The rate of in-hospital mortality in hypoxic hepatitis is very high with studies recording mortalities of 61.5%. It tends to be very uncommon in healthy, young patients with no underlying medical problems. We report here the case of a young healthy athlete who developed heat stroke associated with rhabdomyolysis and hypoxic hepatitis while he was running the final stages of a marathon. The patient required intensive care admission and inotropic support for a few hours after he was admitted with heat stroke. He underwent a rapid recovery after he was resuscitated with fluids. N-acetyl cysteine was also given during the acute stage of the hepatitis. This case highlights an uncommon case of hypoxic hepatitis in a young, healthy patient secondary to hypotension and heat stroke. Inotropic support might have precipitated the hypoxic hepatitis in this young patient.

  14. Cerebral Hemodynamics Patterns by Transcranial Doppler in Patients With Acute Liver Failure.

    Science.gov (United States)

    Abdo, A; Pérez-Bernal, J; Hinojosa, R; Porras, F; Castellanos, R; Gómez, F; Gutiérrez, J; Castellanos, A; Leal, G; Espinosa, N; Gómez-Bravo, M

    2015-11-01

    About half of patients with acute liver failure (ALF) show clinical signs of cerebral edema and intracranial hypertension. Neuroimaging diagnostics and electroencephalography have poor correlation with intracranial pressure measurement. The objective of this study was to characterize the cerebral hemodynamics patterns with transcranial Doppler (TCD) sonography in patients with ALF. We studied 21 patients diagnosed with ALF, admitted to the intensive care unit (ICU) at the Centro de Investigaciones Médico Quirúrgicas of Cuba. All of these patients had a TCD performed on arrival at ICU, evaluating the following: systolic (SV), diastolic (DV), and medium (MV) flows velocities and pulsatility index (PI) in right middle cerebral artery (RMCA) via temporal windows. The sonographic patterns of cerebral hemodynamics were as follows: low-flow, 12 patients (57.1%); high resistance, 5 patients (23.8%); and hyperemic, 4 patients (19%). Patients who died while waiting had lower MV RMCA (56.1 vs 58.1 cm/s) and higher PI (1.71 vs 1.41) than patients who could undergo transplantation (P = .800 and P = .787, respectively). In patients diagnosed with ALF admitted to the ICU the predominating cerebral hemodynamic pattern was low-flow with resistance increase. The TCD was shown to be a useful tool in the initial evaluation for prognosis and treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue

    International Nuclear Information System (INIS)

    Pohjanvirta, Raimo; Boutros, Paul C.; Moffat, Ivy D.; Linden, Jere; Wendelin, Dominique; Okey, Allan B.

    2008-01-01

    Acute progressive feed restriction (APFR) represents a specific form of caloric restriction in which feed availability is increasingly curtailed over a period of a few days to a few weeks. It is often used for control animals in toxicological and pharmacological studies on compounds causing body weight loss to equalize weight changes between experimental and control groups and thereby, intuitively, to also set their metabolic states to the same phase. However, scientific justification for this procedure is lacking. In the present study, we analyzed by microarrays the impact on hepatic gene expression in rats of two APFR regimens that caused identical diminution of body weight (19%) but differed slightly in duration (4 vs. 10 days). In addition, white adipose tissue (WAT) was also subjected to the transcriptomic analysis on day-4. The data revealed that the two regimens led to distinct patterns of differentially expressed genes in liver, albeit some major pathways of energy metabolism were similarly affected (particularly fatty acid and amino acid catabolism). The reason for the divergence appeared to be entrainment by the longer APFR protocol of peripheral oscillator genes, which resulted in derailment of circadian rhythms and consequent interaction of altered diurnal fluctuations with metabolic adjustments in gene expression activities. WAT proved to be highly unresponsive to the 4-day APFR as only 17 mRNA levels were influenced by the treatment. This study demonstrates that body weight is a poor proxy of metabolic state and that the customary protocols of feed restriction can lead to rhythm entrainment

  16. Liver cirrhosis is a risk factor of repeat acute hemorrhagic rectal ulcer in intensive care unit patients

    Directory of Open Access Journals (Sweden)

    Pi-Kai Chang

    2014-01-01

    Full Text Available Background: Acute hemorrhagic rectal ulcer (AHRU can be found in patients with severe comorbid illness, who are bedridden for a long time. Per anal suturing is a quick and feasible treatment. However, recurrent bleeding occurs frequently after suture ligation of a bleeder and can be life-threatening. However, the risk factor for recurrent bleeding is not well known. Our study tries to clarify the risk factor of repeat AHRU in Intensive Care Unit (ICU patients. Materials and Methods: From January 2004 to December 2009, the medical records of 32 patients, who were admitted to the ICU of the Tri-Service General Hospital, a tertiary referral center in Taiwan, and who underwent per anal suturing of acute hemorrhagic rectal ulcer were retrospectively reviewed. Results: Of the 96 patients who received emergency treatment for acute massive hematochezia, 32 patients were diagnosed with AHRU. Eight (25% patients had recurrent bleeding following suture ligation of AHRU and underwent a reoperation; no patient had recurrent bleeding after the second operation. The duration from the first hematochezia attack to surgery (P = 0.04, liver cirrhosis (P = 0.002, and coagulopathy (P = 0.01 were the risk factors of recurrent bleeding after suture ligation of a bleeder. Multivariate logistic regression analysis indicated that liver cirrhosis (OR = 37.77, P = 0.014 was an independent risk factor for recurrent bleeding. Conclusion: AHRU could be a major cause of acute massive hematochezia in patients with severe illness. Our data showed that per anal suturing could quickly and effectively control bleeding. We found that liver cirrhosis was an independent risk factor for recurrent bleeding. Therefore, treatment of a liver cirrhosis patient with AHUR should be more aggressive, such as, early detection and proper suture ligation.

  17. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes

    International Nuclear Information System (INIS)

    Parkinson, Andrew; Mudra, Daniel R.; Johnson, Cory; Dwyer, Anne; Carroll, Kathleen M.

    2004-01-01

    We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase (CYP1A2) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6β-hydroxylase (CYP3A4) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in CYP3A4 activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain CYP3A4 substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of CYP2A6, CYP2B6, and CYP2C8 and half the activity of CYP1A2, although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with β-naphthoflavone, an inducer of CYP1A2, phenobarbital or rifampin, both of which induce CYP2B6, CYP2C9, CYP2C19, and CYP3A4, albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, CYP3A4 induction in

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

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    Jamshid Vafaeimanesh

    2013-01-01

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

  19. Hepatoprotective Effect of Terminalia chebula against t-BHP-Induced Acute Liver Injury in C57/BL6 Mice

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    Min-Kyung Choi

    2015-01-01

    Full Text Available We aimed to identify the hepatoprotective effects of Terminalia chebula water extract (TCW and its corresponding pharmacological actions using C57/BL6 mice model of tert-butylhydroperoxide-(t-BHP- induced acute liver injury. Mice were orally administered with TCW (0, 50, 100, or 200 mg/kg or gallic acid (100 mg/kg for 5 days before t-BHP (2.5 mM/kg injection. Liver enzymes, histopathology, oxidative stress parameters, antioxidant components, and inflammatory cytokines were examined 18 h after t-BHP injection. t-BHP injection caused dramatic elevation of serum AST, ALT, and LDH level, while TCW pretreatment notably attenuated these elevations. Inflammatory cytokines including TNF-α, IL-1β, and IL-6 were notably increased in hepatic tissues, and then these were efficiently attenuated by TCW pretreatment. t-BHP injection notably increased malondialdehyde, total reactive oxygen species, and nitric oxide in the liver tissue, while it markedly dropped the antioxidant activities including total antioxidant capacity, total glutathione contents, glutathione peroxidase, superoxide dismutase, and catalase. TCW pretreatment remarkably ameliorated these alterations, and these effects were relevant to gene expressions. Histopathological examinations supported the above findings. Collectively, these findings well prove that TCW beneficially prevents acute and severe liver injury and clarify its corresponding mechanisms involved in the inhibition of oxidative stress and inflammatory cytokines.

  20. The sinusoidal lining cells in "normal" human liver. A scanning electron microscopic investigation

    DEFF Research Database (Denmark)

    Horn, T; Henriksen, Jens Henrik Sahl; Christoffersen, P

    1986-01-01

    The scanning electron microscopic was used to study the fenestrations of human liver sinusoids. Thirteen biopsies, where light microscopy and transmission electron microscopy revealed normal sinusoidal architecture, were investigated. The number of fenestrae was calculated in acinar zone 3...

  1. Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

    Science.gov (United States)

    Szpinda, Michał; Paruszewska-Achtel, Monika; Mila-Kierzenkowska, Celestyna; Elminowska-Wenda, Gabriela; Dombek, Małgorzata; Szpinda, Anna; Badura, Mateusz

    2015-01-01

    Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18–30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm3 at 18–21 weeks through 14.36 cm3 at 22–25 weeks to 20.77 cm3 at 26–30 weeks, according to the following regression: y = −26.95 + 1.74 × age ± Z  × (−3.15 + 0.27 × age). The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm3 at 18–21 weeks through 28.21 cm3 at 22–25 weeks to 49.69 cm3 at 26–30 weeks. There was a strong relationship (r = 0.91, p hydrostatic (x) and indirect (y) methods, expressed by y = −0.05 + 2.16x  ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias. PMID:26413551

  2. Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival.

    Science.gov (United States)

    Hang, Hua-Lian; Liu, Xin-Yu; Wang, Hai-Tian; Xu, Ning; Bian, Jian-Min; Zhang, Jian-Jun; Xia, Lei; Xia, Qiang

    2017-11-15

    Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of β-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote β-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis

    NARCIS (Netherlands)

    Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas E.; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger T.; Schipper, Marguerite E. I.; Verheem, André; Wijmenga, Cisca; Gooszen, Hein G.; van Erpecum, Karel J.

    2014-01-01

    Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the

  4. Distribution of trans-resveratrol and its metabolites after acute or sustained administration in mouse heart, brain, and liver.

    Science.gov (United States)

    Menet, Marie-Claude; Baron, Stephanie; Taghi, Meryam; Diestra, Remi; Dargère, Delphine; Laprévote, Olivier; Nivet-Antoine, Valérie; Beaudeux, Jean-Louis; Bédarida, Tatiana; Cottart, Charles-Henry

    2017-08-01

    Trans-resveratrol is widely studied for its potentially beneficial effects on numerous disorders. It is rapidly metabolized and its metabolites can exhibit biological activity. The present study aimed to investigate whether acute or sustained trans-resveratrol administration impacted on the distribution of trans-resveratrol and its metabolites in brain, heart, and liver. We used ultra-HPLC quadrupole-TOF (UHPLC-Q-TOF) in a full-scan mode to identify and assess large numbers of resveratrol metabolites. For acute intake, mice were overfed with a single dose of trans-resveratrol (150 mg/kg) and organs were collected after 30 and 60 min. For sustained intake, trans-resveratrol was given in the chow (0.04% w/w corresponding to 40 mg/kg/day), and plasma and the organs were collected after 3 months of this resveratrol diet. We found that trans-resveratrol-3-O-glucuronide and resveratrol-3-sulfate were the main metabolites found after acute intake, and free trans-resveratrol (in the brain and heart) and dihydroresveratrol derivatives were found after sustained administration CONCLUSIONS: Our results show notable differences between acute and sustained administration of trans-resveratrol and distribution of trans-resveratrol and its metabolites in mouse heart, brain, and liver. The results suggest a strategy for development of galenic forms of resveratrol. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Role of Vitamin C As A Potent Antioxidant in Acute Radiation Induced Liver Disease (RILD) Among Male Albino Rats

    International Nuclear Information System (INIS)

    Ezz El Arab, A.; Ayad, S.K.Y.; El Fouly, A.

    2012-01-01

    Recent studies demonstrated the role of vitamin C as antioxidant in alleviating organ damage caused by gamma irradiation. The present study was conducted to find out the effect of vitamin C on liver biochemical functions such as serum ALT, AST, albumin and bilirubin after experimental liver damage induced by gamma irradiation. Rats irradiated with gamma radiation were used as a model of liver injury terminating with necro inflammatory activity and acute hepatitis. Forty male albino rats were classified into 6 groups (G0-G5). G0 included 8 male albino rats that were divided to 2 subgroups (4 rats/subgroup). Both subgroups were exposed to gamma irradiation with 6 Gy as a single dose. The first subgroup was left for 3 weeks then serum and liver samples were collected while in the second subgroup, 2 rats were died and the remaining 2 rats were left for 6 weeks then serum and liver samples were collected. G1 was the negative control while in the rest groups, the whole body of rats was exposed to gamma irradiation of dose 8 Gy divided to 2 doses (4 Gy/one dose) at one week interval in between. G2 included 12 albino rats divided into 3 subgroups (4 rats/subgroup). The whole body of albino rats of G2 was exposed to 8 Gy gamma irradiation that divided as mentioned before. Serum and liver samples were collected after one day, two days and four days after last dose of irradiation. G3 also included 8 rats that were divided into 2 subgroups (4 rats/subgroup) and whole body was exposed to 8 Gy gamma irradiation that were divided as mentioned before. Serum and liver samples were collected after one week for one subgroup and 2 weeks for other subgroup after last dose of irradiation. The rest 2 groups (4 rats/group) were exposed to 8Gy gamma irradiation divided as before, but the rats in one group were orally supplemented with low dose of vitamin C. G4 and the others were supplemented with high dose of vitamin C for 2 weeks starting after last dose of irradiation (G5) then serum

  6. Methods of measuring metabolism during surgery in humans: focus on the liver-brain relationship.

    Science.gov (United States)

    Battezzati, Alberto; Bertoli, Simona

    2004-09-01

    The purpose of this work is to review recent advances in setting methods and models for measuring metabolism during surgery in humans. Surgery, especially solid organ transplantation, may offer unique experimental models in which it is ethically acceptable to gain information on difficult problems of amino acid and protein metabolism. Two areas are reviewed: the metabolic study of the anhepatic phase during liver transplantation and brain microdialysis during cerebral surgery. The first model offers an innovative approach to understand the relative role of liver and extrahepatic organs in gluconeogenesis, and to evaluate whether other organs can perform functions believed to be exclusively or almost exclusively performed by the liver. The second model offers an insight to intracerebral metabolism that is closely bound to that of the liver. The recent advances in metabolic research during surgery provide knowledge immediately useful for perioperative patient management and for a better control of surgical stress. The studies during the anhepatic phase of liver transplantation have showed that gluconeogenesis and glutamine metabolism are very active processes outside the liver. One of the critical organs for extrahepatic glutamine metabolism is the brain. Microdialysis studies helped to prove that in humans there is an intense trafficking of glutamine, glutamate and alanine among neurons and astrocytes. This delicate network is influenced by systemic amino acid metabolism. The metabolic dialogue between the liver and the brain is beginning to be understood in this light in order to explain the metabolic events of brain damage during liver failure.

  7. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-01-01

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  8. Expression pattern of thymosin beta 4 in the adult human liver

    Directory of Open Access Journals (Sweden)

    S. Nemolato

    2011-09-01

    Full Text Available Thymosin beta-4 (Tβ4 is a member of beta-thymosins, a family of small peptides involved in polymerization of G-actin, and in many critical biological processes including apoptosis, cell migration, angiogenesis, and fibrosis. Previous studies in the newborn liver did not reveal any significant reactivity for Tβ4 during the intrauterine life. The aim of the present study was to investigate by immunohistochemistry Tβ4 expression in the adult normal liver. Thirty-five human liver samples, including 11 needle liver biopsies and 24 liver specimens obtained at autopsy, in which no pathological change was detected at the histological examination, were immunostained utilizing an anti-Tβ4 commercial antibody. Tβ4 was detected in the hepatocytes of all adult normal livers examined. A zonation of Tβ4 expression was evident in the vast majority of cases. Immunostaining was preferentially detected in zone 3, while a minor degree of reactivity was detected in periportal hepatocytes (zone 1. At higher power, Tβ4-reactive granules appeared mainly localized at the biliary pole of hepatocytes. In cases with a strong immunostaining, even perinuclear areas and the sinusoidal pole of hepatocytes appeared interested by immunoreactivity for Tβ4. The current work first evidences a strong diffuse expression of Tβ4 in the adult human liver, and adds hepatocytes to the list of human cells able to synthesize large amounts of Tβ4 in adulthood. Moreover, Tβ4 should be added to the liver proteins characterized by a zonate expression pattern, in a descending gradient from the terminal vein to the periportal areas of the liver acinus. Identifying the intimate role played by this peptide intracellularly and extracellularly, in physiology and in different liver diseases, is a major challenge for future research focusing on Tβ4.

  9. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  10. Molecular cloning and nucleotide sequence of cDNA for human liver arginase

    International Nuclear Information System (INIS)

    Haraguchi, Y.; Takiguchi, M.; Amaya, Y.; Kawamoto, S.; Matsuda, I.; Mori, M.

    1987-01-01

    Arginase (EC3.5.3.1) catalyzes the last step of the urea cycle in the liver of ureotelic animals. Inherited deficiency of the enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. To facilitate investigation of the enzyme and gene structures and to elucidate the nature of the mutation in argininemia, the authors isolated cDNA clones for human liver arginase. Oligo(dT)-primed and random primer human liver cDNA libraries in λ gt11 were screened using isolated rat arginase cDNA as a probe. Two of the positive clones, designated λ hARG6 and λ hARG109, contained an overlapping cDNA sequence with an open reading frame encoding a polypeptide of 322 amino acid residues (predicted M/sub r/, 34,732), a 5'-untranslated sequence of 56 base pairs, a 3'-untranslated sequence of 423 base pairs, and a poly(A) segment. Arginase activity was detected in Escherichia coli cells transformed with the plasmid carrying λ hARG6 cDNA insert. RNA gel blot analysis of human liver RNA showed a single mRNA of 1.6 kilobases. The predicted amino acid sequence of human liver arginase is 87% and 41% identical with those of the rat liver and yeast enzymes, respectively. There are several highly conserved segments among the human, rat, and yeast enzymes

  11. Metabolism of ethylbenzene by human liver microsomes and recombinant human cytochrome P450s (CYP).

    Science.gov (United States)

    Sams, Craig; Loizou, George D; Cocker, John; Lennard, Martin S

    2004-03-07

    The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were determined in human liver microsomes. The individual cytochrome P450 (CYP) forms catalysing this reaction were identified using selective inhibitors and recombinant preparations of hepatic CYPs. Production of 1-phenylethanol in hepatic microsomes exhibited biphasic kinetics with a high affinity, low Km, component (mean Km = 8 microM; V(max) = 689 pmol/min/mg protein; n = 6 livers) and a low affinity, high Km, component (Km = 391 microM; V(max) = 3039 pmol/min/mg protein; n = 6). The high-affinity component was inhibited 79%-95% (mean 86%) by diethyldithiocarbamate, and recombinant CYP2E1 was shown to metabolise ethylbenzene with low Km (35 microM), but also low (max) (7 pmol/min/pmol P450), indicating that this isoform catalysed the high-affinity component. Recombinant CYP1A2 and CYP2B6 exhibited high V(max) (88 and 71 pmol/min/pmol P450, respectively) and high Km (502 and 219 microM, respectively), suggesting their involvement in catalysing the low-affinity component. This study has demonstrated that CYP2E1 is the major enzyme responsible for high-affinity side chain hydroxylation of ethylbenzene in human liver microsomes. Activity of this enzyme in the population is highly variable due to induction or inhibition by physiological factors, chemicals in the diet or some pharmaceuticals. This variability can be incorporated into the risk assessment process to improve the setting of occupational exposure limits and guidance values for biological monitoring.

  12. A new liver function test using the asialoglycoprotein-receptor system on the liver cell membrane, 3

    International Nuclear Information System (INIS)

    Hazama, Hiroshi; Kawa, Soukichi; Kubota, Yoshitsugu

    1986-01-01

    We evaluated the vilidity of a new liver function test using liver scintigraphy based on the asialoglycoprotein (ASGP) receptor system on the liver cell membrane in rats with galactosamine-induced acute liver disorder and those with carbon tetra-chloride-induced chronic liver disorder. Neoglycoprotein (GHSA) produced by combining human serum albumin with 32 galactose units was labeled with 99m Tc and administered (50 μg/100 g body weight) to rats with acute or chronic liver disorder. Clearance curves were produced based on liver scintigrams and analysed using the two-compartment model to obtain parameters. In acute liver disorder, the prolongation of 99m Tc-GHSA clearance and the decrease in ASGP receptor activities correlated well to the increase in serum GOT and the decrease in the esterified to total cholesterol ratio (E/T ratio); in chronic liver disorder, they correlated significantly to the increase in the content of liver hydroxyproline (Hyp) which increased in proportion to the severity of liver fibrosis studied histologically, and to the decrease in the contents of cytochrome P-450 and cytochrome b 5 in liver microsomes. Significant correlation was observed between the prolongation of 99m Tc-GHSA clearance and the decrease in ASGP receptor activities in both acute and chronic liver disorders. These findings indicate that the measurement of 99m Tc-GHSA clearance can be a new liver function test sensitively reflecting the severity of liver damage. (author)

  13. Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice.

    Science.gov (United States)

    Shimizu, Makiko; Suemizu, Hiroshi; Mitsui, Marina; Shibata, Norio; Guengerich, F Peter; Yamazaki, Hiroshi

    2017-10-01

    1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice. 3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans. 4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

  14. An analysis of predictive factors for concurrent acute-on-chronic liver failure and hepatorenal syndrome

    Directory of Open Access Journals (Sweden)

    CHEN Yanfang

    2015-09-01

    Full Text Available ObjectiveTo learn the clinical characteristics of concurrent acute-on-chronic liver failure (ACLF and hepatorenal syndrome (HRS, and to investigate the predictive factors for HRS in patients with ACLF. MethodsA total of 806 patients with ACLF who were admitted to our hospital from January 2012 to May 2014 were selected and divided into two groups according to the incidence of concurrent HRS. Clinical indices and laboratory test results were analyzed in the two groups, and the multivariate logistic regression analysis was used to figure out independent indices for the prediction of HRS in patients with ACLF. A prediction model was established and the receiver operating characteristic curve was drawn to evaluate the accuracy of the prediction model. Comparison of continuous data between the two groups was made by t test, and comparison of categorical data between the two groups was made by χ2 test. ResultsIn all patients with ACLF, 229 had HRS and 577 had no HRS. The univariate logistic regression analysis showed that hepatic encephalopathy, peritonitis, infection, age, cystatin C (Cys-C, serum creatinine (SCr, blood urea nitrogen, albumin, prealbumin, total bilirubin, direct bilirubin, total cholesterol, K+, Na+, phosphorus, Ca2+, prothrombin time, prothrombin activity, international normalized ratio, and hematocrit were significant predictive factors for HRS. The multivariate logistic regression analysis showed that concurrent peritonitis, Cys-C, SCr, and HCO3- were independent predictive factors for HRS in patients with ACLF (OR=3.155, P<0.01; OR=30.773, P<0.01; OR=1062, P<0.01; OR=0.915, P<0.05. The model was proved of great value in prediction. ConclusionConcurrent peritonitis, Cys-C, SCr, and HCO3- are effective predictive factors for HRS in patients with ACLF.

  15. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.

    Science.gov (United States)

    Bansal, Ruchi; Prakash, Jai; De Ruiter, Marieke; Poelstra, Klaas

    2014-04-10

    Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFβR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFβR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Acute effects of ethanol in the control of protein synthesis in isolated rat liver cells

    International Nuclear Information System (INIS)

    Girbes, T.; Susin, A.; Ayuso, M.S.; Parrilla, R.

    1983-01-01

    The acute effect of ethanol on hepatic protein synthesis is a rather controversial issue. In view of the conflicting reports on this subject, the effect of ethanol on protein labeling from L-[ 3 H]valine in isolated liver cells was studied under a variety of experimental conditions. When tracer doses of the isotope were utilized, ethanol consistently decreased the rate of protein labeling, regardless of the metabolic conditions of the cells. This inhibition was not prevented by doses of 4-methylpyrazole large enough to abolish all the characteristic metabolic effects of ethanol, and it was not related to perturbations on the rates of L-valine transport and/or proteolysis. When ethanol was tested in the presence of saturating doses of L-[ 3 H]valine no effect on protein labeling was observed. These observations suggest that the ethanol effect in decreasing protein labeling from tracer doses of the radioactive precursor does not reflect variations in the rate of protein synthesis but reflects changes in the specific activity of the precursor. These changes probably are secondary to variations in the dimensions of the amino acid pool utilized for protein synthesis. Even though it showed a lack of effect when tested alone, in the presence of saturating doses of the radioactive precursor ethanol inhibited the stimulatory effects on protein synthesis mediated by glucose and several gluconeogenic substrates. This effect of ethanol was not prevented by inhibitors of alcohol dehydrogenase, indicating that a shift of the NAD system to a more reduced state is not the mediator of its action. It is suggested that ethanol probably acted by changing the steady-state levels of some common effector(s) generated from the metabolism of all these fuels or else by preventing the inactivation of a translational repressor

  17. Increased blood-brain transfer in a rabbit model of acute liver failure

    International Nuclear Information System (INIS)

    Horowitz, M.E.; Schafer, D.F.; Molnar, P.; Jones, E.A.; Blasberg, R.G.; Patlak, C.S.; Waggoner, J.; Fenstermacher, J.D.

    1983-01-01

    The blood-to-brain transfer of [ 14 C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [ 14 C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [ 14 C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy

  18. Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure.

    Science.gov (United States)

    Rama Rao, Kakulavarapu V; Verkman, A S; Curtis, Kevin M; Norenberg, Michael D

    2014-03-01

    Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6% ± 0.3 and 2.3 ± 0.4%, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF. Published by Elsevier Inc.

  19. Pyrethroid insecticide lambda-cyhalothrin and its metabolites induce liver injury through the activation of oxidative stress and proinflammatory gene expression in rats following acute and subchronic exposure.

    Science.gov (United States)

    Aouey, Bakhta; Derbali, Mohamed; Chtourou, Yassine; Bouchard, Michèle; Khabir, Abdelmajid; Fetoui, Hamadi

    2017-02-01

    Lambda-cyhalothrin (LTC) [α-cyano-3-phenoxybenzyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclo-propanecarboxylate] is a synthetic type II pyrethroid insecticide commonly used in residential and agricultural areas. The potential hepatotoxicity of pyrethroids remains unclear and could easily be assessed by measuring common clinical indicators of liver disease. To understand more about the potential risks for humans associated with LTC exposure, male adult rats were orally exposed to 6.2 and 31.1 mg/kg bw of LTC for 7, 30, 45, and 60 days. Histopathological changes and alterations of main parameters related to oxidative stress and inflammatory responses in the liver were evaluated. Further, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] in the liver tissues were identified and quantified by ultra-high-performance liquid chromatography coupled to quadripole time-of-flight mass spectrometry (UHPLC-MS-Q-ToF). Results revealed that LTC exposure significantly increased markers of hepatic oxidative stress in a time-dependent and dose-dependent manner, and this was associated with an accumulation of CFMP and 3-PBA in the liver tissues. In addition, the levels of tumor necrosis factor-α (TNF-α) and interleukin (IL-6 and IL-1β) gene expressions were significantly increased in the liver of exposed rats compared to controls. Correlation analyses revealed that CFMP and 3-PBA metabolite levels in the liver tissues were significantly correlated with the indexes of oxidative stress, redox status, and inflammatory markers in rats exposed to lambda-cyhalothin. Overall, this study provided novel evidence that hepatic damage is likely due to increased oxidative stress and inflammation under the condition of acute and subchronic exposure to lambda-cyhalothrin and that LTC metabolites (CFMP and 3-PBA) could be used as

  20. Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

    Science.gov (United States)

    Nakagawa, Shin-ichiro; Hirata, Yuichi; Kameyama, Takeshi; Tokunaga, Yuko; Nishito, Yasumasa; Hirabayashi, Kazuko; Yano, Junichi; Ochiya, Takahiro; Tateno, Chise; Tanaka, Yasuhito; Mizokami, Masashi; Tsukiyama-Kohara, Kyoko; Inoue, Kazuaki; Yoshiba, Makoto; Takaoka, Akinori; Kohara, Michinori

    2013-01-01

    The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

  1. Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

    Directory of Open Access Journals (Sweden)

    Shin-ichiro Nakagawa

    Full Text Available BACKGROUND & AIMS: The interferon (IFN system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV and hepatitis B virus (HBV. METHODS: This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC. Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs in the livers and sera of these humanized chimeric mice. RESULTS: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1, suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. CONCLUSIONS: These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

  2. Evidences for CYP3A4 autoactivation in the desulfuration of dimethoate by the human liver.

    Science.gov (United States)

    Buratti, Franca M; Testai, Emanuela

    2007-11-20

    Dimethoate (DIM) is an organophosphorothionate (OPT) pesticide used worldwide as a systemic insecticide and acaricide. It is characterized by low-to-moderate acute mammalian toxicity; similarly to the other OPT pesticides, its mode of action is mediated by the inhibition of acetylcholinesterase (AChE), exerted by its toxic metabolite dimethoate-oxon or omethoate (OME), which is also used as a direct acting pesticide. Human hepatic DIM bioactivation to the toxic metabolite OME has been characterized by using c-DNA expressed human CYPs and human liver microsomes (HLM) also in the presence of CYP-specific chemical inhibitors, with a method based on AChE inhibition. The obtained kinetic parameters and AChE IC(50) have been compared with those previously obtained with other OPTs, indicating a lower efficiency in DIM desulfuration reaction and a lower potency in inhibiting AChE. Results showed that, similarly to the other OPTs tested so far, at low DIM concentration OME formation is mainly catalysed by CYP1A2, while the role of 3A4 is relevant at high DIM levels. Differently from the other OPTs, DIM desulfuration reaction showed an atypical kinetic profile, likely due to CYP3A4 autoactivation. The sigmoidicity degree of the activity curve increased with the level of CYP3A4 in HLM or disappeared in the presence of a CYP3A4 chemical inhibitor. This atypical kinetic behaviour can be considered one of the possible explanations for the recent findings that among patients hospitalized following OPT intoxication, DIM ingestion gave different symptoms and more severe poisoning (23.1% of fatal cases versus total) than chlorpyrifos (8% of deaths), which has a lower LD(50) value. Since DIM-poisoned patients poorly responded to pralidoxime, the possibility to use CYP3A4 inhibitors could be considered as a complementary treatment.

  3. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  4. Cloning and characterization of human liver cytosolic beta-glycosidase

    NARCIS (Netherlands)

    De Graaf, M; Van Veen, IC; Van Der Meulen-Muileman, IH; Gerritsen, WR; Pinedo, HM; Haisma, HJ

    2001-01-01

    Cytosolic beta -glucosidase (EC 3.2.1.21) from mammalian liver is a member of the family 1 glycoside hydrolases and is known for its ability to hydrolyse a range of beta -D-glycosides. including beta -D-glucoside acid beta -D-galactoside. We therefore refer to this enzyme as cytosolic beta

  5. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  6. Integrated Assessment of Diclofenac Biotransformation, Pharmacokinetics, and Omics-Based Toxicity in a Three-Dimensional Human Liver-Immunocompetent Coculture System.

    Science.gov (United States)

    Sarkar, Ujjal; Ravindra, Kodihalli C; Large, Emma; Young, Carissa L; Rivera-Burgos, Dinelia; Yu, Jiajie; Cirit, Murat; Hughes, David J; Wishnok, John S; Lauffenburger, Douglas A; Griffith, Linda G; Tannenbaum, Steven R

    2017-07-01

    In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography-tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans. Further characterization of secreted bile acids in the medium revealed that a glycine-conjugated bile acid was a sensitive marker of dose-dependent toxicity in this three-dimensional liver microphysiological system. Protein markers were significantly elevated in the culture medium at high micromolar doses of DCF, which were also observed previously for acute drug-induced toxicity in humans. In this immunocompetent model, lipopolysaccharide treatment evoked an inflammatory response that resulted in a marked increase in the overall number of acute phase proteins. Kupffer cell-mediated cytokine release recapitulated an in vivo proinflammatory response exemplified by a cohort of 11 cytokines that were differentially regulated after lipopolysaccharide induction, including interleukin (IL)-1 β , IL-1Ra, IL-6, IL-8, IP-10, tumor necrosis factor- α , RANTES (regulated on activation normal T cell expressed and secreted), granulocyte colony-stimulating factor, macrophage colony-stimulating factor, macrophage inflammatory protein-1 β , and IL-5. In summary, our findings indicate that three-dimensional liver microphysiological systems may serve as preclinical investigational platforms from the perspective of the discovery of a set of clinically relevant biomarkers including potential reactive metabolites, endogenous bile acids, excreted proteins, and cytokines to predict early drug

  7. Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure-A Retrospective Analysis.

    Science.gov (United States)

    Gerth, Hans U; Pohlen, Michele; Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Hüsing-Kabar, Anna; Wilms, Christian; Maschmeier, Miriam; Kabar, Iyad; Torner, Josep; Pavesi, Marco; Arroyo, Vicente; Banares, Rafael; Schmidt, Hartmut H J

    2017-10-01

    Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial. Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria. Medical Departments of University Hospital Muenster (Germany). This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1-3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial. Standard medical treatment and molecular adsorbent recirculating system. Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2-3). Concerning the

  8. Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

    Science.gov (United States)

    Li, Yan; Zhou, Yanyan; Si, Nan; Han, Lingyu; Ren, Wei; Xin, Shaokun; Wang, Hongjie; Zuo, Ran; Wei, Xiaolu; Yang, Jian; Zhao, Haiyu; Bian, Baolin

    2017-11-01

    Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the in vitro metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids

  9. Visualization of acute liver damage induced by cycloheximide in rats using PET with [(18F]FEDAC, a radiotracer for translocator protein (18 kDa.

    Directory of Open Access Journals (Sweden)

    Akiko Hatori

    Full Text Available Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[(18F]fluoroethyl-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([(18F]FEDAC, a radiotracer specific for translocator protein (18 kDa, TSPO as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [(18F]FEDAC. The uptake of [(18F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [(18F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [(18F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage.

  10. Proteomic analysis of tyrosine phosphorylation during human liver transplantation

    Directory of Open Access Journals (Sweden)

    Boutros Tarek

    2007-01-01

    Full Text Available Abstract Background Ischemia-reperfusion (I/R causes a dramatic reprogramming of cell metabolism during liver transplantation and can be linked to an alteration of the phosphorylation level of several cellular proteins. Over the past two decades, it became clear that tyrosine phosphorylation plays a pivotal role in a variety of important signalling pathways and was linked to a wide spectrum of diseases. Functional profiling of the tyrosine phosphoproteome during liver transplantation is therefore of great biological significance and is likely to lead to the identification of novel targets for drug discovery and provide a basis for novel therapeutic strategies. Results Using liver biopsies collected during the early phases of organ procurement and transplantation, we aimed at characterizing the global patterns of tyrosine phosphorylation during hepatic I/R. A proteomic approach, based on the purification of tyrosine phosphorylated proteins followed by their identification using mass spectrometry, allowed us to identify Nck-1, a SH2/SH3 adaptor, as a potential regulator of I/R injury. Using immunoblot, cell fractionation and immunohistochemistry, we demonstrate that Nck-1 phosphorylation, expression and localization were affected in liver tissue upon I/R. In addition, mass spectrometry identification of Nck-1 binding partners during the course of the transplantation also suggested a dynamic interaction between Nck-1 and actin during I/R. Conclusion Taken together, our data suggest that Nck-1 may play a role in I/R-induced actin reorganization, which was previously reported to be detrimental for the hepatocytes of the transplanted graft. Nck-1 could therefore represent a target of choice for the design of new organ preservation strategies, which could consequently help to reduce post-reperfusion liver damages and improve transplantation outcomes.

  11. Preventive Effects of Dexmedetomidine on the Liver in a Rat Model of Acid-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Velat Şen

    2014-01-01

    Full Text Available The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300–350 g were allocated randomly to four groups. In group 1, normal saline (NS was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI was found to be associated with increased malondialdehyde (MDA, total oxidant activity (TOA, oxidative stress index (OSI, and decreased total antioxidant capacity (TAC. Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P<0.05. The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

  12. Preventive effects of dexmedetomidine on the liver in a rat model of acid-induced acute lung injury.

    Science.gov (United States)

    Sen, Velat; Güzel, Abdulmenap; Şen, Hadice Selimoğlu; Ece, Aydın; Uluca, Unal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

    2014-01-01

    The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

  13. In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells.

    Science.gov (United States)

    Ramachandran, Sarada Devi; Schirmer, Katharina; Münst, Bernhard; Heinz, Stefan; Ghafoory, Shahrouz; Wölfl, Stefan; Simon-Keller, Katja; Marx, Alexander; Øie, Cristina Ionica; Ebert, Matthias P; Walles, Heike; Braspenning, Joris; Breitkopf-Heinlein, Katja

    2015-01-01

    In this study we used differentiated adult human upcyte® cells for the in vitro generation of liver organoids. Upcyte® cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte® process). Proliferating upcyte® cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte® cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured in vitro on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions.

  14. Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

    Science.gov (United States)

    2014-01-01

    Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

  15. A rare cause of acute flaccid paralysis: Human coronaviruses

    OpenAIRE

    Turgay, Cokyaman; Emine, Tekin; Ozlem, Koken; Muhammet, S. Paksu; Haydar, A. Tasdemir

    2015-01-01

    Acute flaccid paralysis (AFP) is a life-threatening clinical entity characterized by weakness in the whole body muscles often accompanied by respiratory and bulbar paralysis. The most common cause is Gullian-Barre syndrome, but infections, spinal cord diseases, neuromuscular diseases such as myasthenia gravis, drugs and toxins, periodic hypokalemic paralysis, electrolyte disturbances, and botulism should be considered as in the differential diagnosis. Human coronaviruses (HCoVs) cause common ...

  16. Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit

    NARCIS (Netherlands)

    R.J. de Knegt (Robert); J. Kornhuber (Johannes); S.W. Schalm (Solko); K. Rusche (K.); P.F. Riederer (Peter); J. Tan (J.)

    1993-01-01

    textabstractBinding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were

  17. Influence of sex and developmental stage on acute hepatotoxic and inflammatory responses to liver procarcinogens in the mouse

    International Nuclear Information System (INIS)

    Hanna, Daniel; Riedmaier, Ariane Emami; Sugamori, Kim S.; Grant, Denis M.

    2016-01-01

    The incidence of liver cancer is higher in men than in women. This sex difference is also observed in murine tumor induction models that result in the appearance of liver tumors in adult mice following their exposure on postnatal days 8 and/or 15 to carcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN). Previous studies performed in adult mice showed that acute hepatotoxic and inflammatory responses to high-dose DEN exposure were greater in males than in females, leading to the suggestion that these responses could account for the sex difference in tumor development. We also recently observed that female but not male mice exposed postnatally to ABP had slightly increased expression of the antioxidant defense genes Nqo1 and Ggt1, which are regulated by the oxidative stress response protein nuclear factor erythroid 2-related factor 2 (NRF2), while expression of Hmox1 was increased in both sexes. The goal of the present study was therefore to compare selected acute hepatotoxic, inflammatory and oxidative stress defense responses to ABP, DEN, or the prototype hepatotoxicant carbon tetrachloride (CCl 4 ), in male and female mice exposed to these chemicals either postnatally or as adults. Exposure of adult mice to ABP, DEN or CCl 4 produced a 2-fold greater acute elevation in serum levels of the hepatotoxicity biomarker alanine aminotransferase (ALT) in males than in females, while levels of the inflammatory biomarker interleukin-6 (IL-6) showed no sex difference. However, treatment of immature mice with either ABP or DEN using standard tumor-inducing postnatal exposure protocols produced no increase in serum ALT or IL-6 levels in either males or females, while CCl 4 produced a 40-fold ALT elevation but with no sex difference. Basal expression of the NRF2-responsive gene Nqo1 was higher in adult females than in males, but there was no sex difference in basal expression of Ggt1 or Hmox1. Sexually immature animals showed no sex difference in basal

  18. Patients with HBV-related acute-on-chronic liver failure have increased concentrations of extracellular histones aggravating cellular damage and systemic inflammation.

    Science.gov (United States)

    Li, X; Gou, C; Yao, L; Lei, Z; Gu, T; Ren, F; Wen, T

    2017-01-01

    Acute-on-chronic liver failure (ACLF) is the most common type of liver failure and associated with grave consequences. Systemic inflammation has been linked to its pathogenesis and outcome, but the identifiable triggers are absent. Recently, extracellular histones, especially H4, have been recognized as important mediators of cell damage in various inflammatory conditions. This study aimed to investigate whether extracellular histones have clinical implications in patients with hepatitis B virus (HBV)-related ACLF. One hundred and twelve patients with HBV-related ACLF, 90 patients with chronic hepatitis B, 88 patients with HBV-related liver cirrhosis and 40 healthy volunteers were entered into this study. Plasma histone H4 levels, cytokine profile and clinical data were obtained. Besides, patient's sera were incubated overnight with human L02 hepatocytes or monocytic U937 cells in the presence or absence of antihistone H4 antibody, and cellular damage and cytokine production were evaluated. We found that plasma histone H4 levels were greatly increased in patients with ACLF as compared with chronic hepatitis B, liver cirrhosis and healthy control subjects and were significantly associated with disease severity, systemic inflammation and outcome. Notably, ACLF patients' sera incubation decreased cultured L02 cell integrity and induced profound cytokine production in the supernatant of U937 cells. Antihistone H4 antibody treatment abrogated these adverse effects, thus confirming a cause-effect relationship between extracellular histones and organ injury/dysfunction. The data support the hypothesis that the increased extracellular histone levels in ACLF patients may aggravate disease severity by inducing cellular injury and systemic inflammation. Histone-targeted therapies may have potentially interventional value in clinical practice. © 2016 John Wiley & Sons Ltd.

  19. Effects of Acute Exercise and Chronic Exercise on the Liver Leptin-AMPK-ACC Signaling Pathway in Rats with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Xuejie Yi

    2013-01-01

    Full Text Available Aim. To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ. Methods. Animals were classified into control (CON, diabetes (DC, diabetic chronic exercise (DCE, and diabetic acute exercise (DAE groups. Results. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPKα1/2, AMPKα1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPKα1/2, AMPKα2, AMPKα1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC. Conclusion. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver.

  20. Acute liver failure due to natural killer-like T-cell leukemia/lymphoma: A case report and review of the Literature

    Institute of Scientific and Technical Information of China (English)

    Evan S Dellon; Shannon R Morris; Wozhan Tang; Cherie H Dunphy; Mark W Russo

    2006-01-01

    Acute liver failure (ALF) is a medical emergency requiring immediate evaluation for liver transplantation. We describe an unusual case of a patient who presented with ascites, jaundice, and encephalopathy and was found to have ALF due to natural killer (NK)-like T cell leukemia/lymphoma. The key immunophenotype was CD2+, CD3+, CD7+, CD56+. This diagnosis, which was based on findings in the peripheral blood and ascitic fluid, was confirmed with liver biopsy, and was a contraindication to liver transplantation. A review of the literature shows that hematologic malignancies are an uncommon cause of fulminant hepatic failure, and that NK-like T-cell leukemia/lymphoma is a relatively recently recognized entity which is characteristically CD3+ and CD56+. This case demonstrates that liver biopsy is essential in diagnosing unusual causes of acute liver failure, and that infiltration of the liver with NK-like T-cell lymphoma/leukemia can cause acute liver failure.

  1. Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.

    Science.gov (United States)

    Creput, Caroline; Le Friec, Gaëlle; Bahri, Rajia; Amiot, Laurence; Charpentier, Bernard; Carosella, Edgardo; Rouas-Freiss, Nathalie; Durrbach, Antoine

    2003-11-01

    Human leukocyte antigen G (HLA-G) is a regulatory molecule that is expressed in the cytotrophoblast during implantation and is thought to allow the tolerance and the development of the semiallogeneic embryo. In vitro, HLA-G inhibits natural killer (NK) cell and CD8 T-cell cytotoxicity. HLA-G also decreases CD4 T-cell expansion. This suggests that it participates in the acceptance of allogeneic organ transplants in humans. We here describe the detection of high concentration of HLA-G in serum from liver-kidney transplant patients, but not in kidney transplant patients. This finding is supported by the ectopic expression of HLA-G in graft biopsies. Finally, its association with a low number of acute transplant rejections, especially in liver-kidney transplant patients led us to propose that HLA-G may serve to monitor transplant patients who are likely to accept their allograft and, thus, may benefit of a reduced immunosuppressive treatment.

  2. Netrin-1 and semaphorin 3A predict the development of acute kidney injury in liver transplant patients.

    Directory of Open Access Journals (Sweden)

    Lidia Lewandowska

    Full Text Available Acute kidney injury (AKI is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients' samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8 ± 112.4 pg/mg creatinine, semaphorin 3A (847.9 ± 93.3 pg/mg creatinine and NGAL (2172.2 ± 378.1 ng/mg creatinine levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732 only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364. These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.

  3. Acute cardiovascular toxicity of sterilizers, PHMG, and PGH: severe inflammation in human cells and heart failure in zebrafish.

    Science.gov (United States)

    Kim, Jae-Yong; Kim, Hak Hyeon; Cho, Kyung-Hyun

    2013-06-01

    In 2011, dozens of children and pregnant women in Korea died by exposure to sterilizer for household humidifier, such as Oxy(®) and Cefu(®). Until now, however, it remains unknown how the sterilizer affect the human health to cause the acute deaths. To find its toxicity for organ, we investigated the putative toxicity of the sterilizer in the cardiovascular system. The sterilizers, polyhexamethylene guanidine phosphate (PHMG, Cefu(®)), and oligo-[2-(2-ethoxy)-ethoxyethyl)-guanidinium-chloride (PGH, Oxy(®)) were treated to human lipoproteins, macrophages, and dermal fibroblast cells. The PGH and PHMG at normal dosages caused severe atherogenic process in human macrophages, cytotoxic effect, and aging in human dermal cell. Zebrafish embryos, which were exposed to the sterilizer, showed early death with acute inflammation and attenuated developmental speed. All zebrafish exposed to the working concentration of PHMG (final 0.3 %) and PGH (final 10 mM) died within 70 min and displayed acute increases in serum triacylglycerol level and fatty liver induction. The dead zebrafish showed severe accumulation of fibrous collagen in the bulbous artery of the heart with elevation of reactive oxygen species. In conclusion, the sterilizers showed acute toxic effect in blood circulation system, causing by severe inflammation, atherogenesis, and aging, with embryo toxicity.

  4. A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax.

    Science.gov (United States)

    March, Sandra; Ng, Shengyong; Velmurugan, Soundarapandian; Galstian, Ani; Shan, Jing; Logan, David J; Carpenter, Anne E; Thomas, David; Sim, B Kim Lee; Mota, Maria M; Hoffman, Stephen L; Bhatia, Sangeeta N

    2013-07-17

    The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Human Adipose Tissue Derived Stem Cells Promote Liver Regeneration in a Rat Model of Toxic Injury

    Directory of Open Access Journals (Sweden)

    Eva Koellensperger

    2013-01-01

    Full Text Available In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20. Injection of cell culture medium performed in group 2 (n = 20 served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017, total protein (P < 0.031, glutamic oxaloacetic transaminase (P < 0.001, and lactate dehydrogenase (P < 0.04 levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.

  6. Toxicity levels to humans during acute exposure to hydrogen fluoride

    International Nuclear Information System (INIS)

    Halton, D.M.; Dranitsaris, P.; Baynes, C.J.

    1984-11-01

    A literature review was conducted of the acute toxicity of hydrogen fluoride (HF) with emphasis on the effects of inhalation of gaseous HF. The data and findings of the relevant references were summarized under four categories: animal studies, controlled human studies, community exposure and industrial exposure. These were critically reviewed and then lethal concentration-time relationships were developed for humans, corresponding to LCsub(LO), LCsub(10) and LCsub(50) levels. The effects of age, health and other physiological variables on the sensitivity to HF were discussed, as well as antagonistic and synergistic effects with other substances

  7. Effect of riluzole on acute pain and hyperalgesia in humans

    DEFF Research Database (Denmark)

    Hammer, N A; Lillesø, J; Pedersen, J L

    1999-01-01

    Riluzole modulates several transmitter systems which may be involved in nociception. Antinociceptive effects have been shown in animal studies, but there are no human data. Therefore, we have examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal...... injury on the distal leg (47 degrees C, 7 min, 12.5 cm2) in 20 healthy volunteers. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and thermodes. We used a randomized, double-blind, placebo-controlled design, and subjects received riluzole 100 mg or placebo for 2 days...

  8. Determination of cobalt in human liver by atomic absorption spectrometry with electrothermal atomization

    International Nuclear Information System (INIS)

    Caldas, E.D.; Gine-Rosias, M.F.; Dorea, J.G.

    1991-01-01

    A detailed study of the use of electrothermal atomic absorption spectrometry for the determination of cobalt in human liver is described. Comparisons of sample digestion using nitric acid or nitric acid plus perchloric acid, atomization procedures and the application of palladium and magnesium nitrate chemical modifiers were studied using NBS SRM 1577a Bovine Liver. The best results were achieved with sample decomposition in nitric acid, atomization from the tube wall and no chemical modifier. Cobalt was determined in 90 samples of livers from foetuses and deceased newborns using the standard addition method with an average recovery of 99.8%. (author). 30 refs.; 4 figs.; 2 tabs

  9. AMC-Bio-Artificial Liver culturing enhances mitochondrial biogenesis in human liver cell lines: The role of oxygen, medium perfusion and 3D configuration

    NARCIS (Netherlands)

    Adam, Aziza A. A.; van Wenum, Martien; van der Mark, Vincent A.; Jongejan, Aldo; Moerland, Perry D.; Houtkooper, Riekelt H.; Wanders, Ronald J. A.; Oude Elferink, Ronald P.; Chamuleau, Robert A. F. M.; Hoekstra, Ruurdtje

    2017-01-01

    Human liver cell lines, like HepaRG and C3A, acquire higher functionality when cultured in the AMC-Bio-Artificial Liver (AMC-BAL). The three main differences between BAL and monolayer culture are the oxygenation (40% vs 20%O2), dynamic vs absent medium perfusion and 3D vs 2D configuration. Here, we

  10. Nucleic acid metabolism in human chronic liver disease by in vitro autoradiography. I. Altered RNA metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, T [Okayama Univ. (Japan). School of Medicine

    1976-06-01

    Biopsy liver specimens from healthy control subjects (N=5) and patients with various liver diseases (N=43) were investigated by the vitro autoradiography. The Leevy technique of adding /sup 3/H-5-uridine (/sup 3/H-U) to the incubation medium was used. In healthy subjects labeling with /sup 3/H-U was observed mostly in hepatocytes and Kupffer cells and the frequency of /sup 3/H-U labeled cells was extremely high. Higher frequencies of labeled fibrocytes and endothelial cells of the blood vessel were found in acute hepatitis than in control subjects. In the active form of chronic hepatitis, significantly higher counts of labeled fibrocytes, ductular cells and lymphocytes were found. In patients with acute hepatitis or the inactive form of chronic hepatitis, only a few labeled lymphocytes were observed. Larger numbers of labeled fibrocytes were found in patients with chronic hepatitis with sublobular hepatic necrosis, than in patients with the active form of chronic hepatitis. In cirrhotic livers, marked increases of labeled ductular cells, fibrocytes and bile duct cells were found. No significant labeling differences were observed in the hepatocytes of various liver diseases. In chronic hepatitis with sublobular hepatic necrosis, a more significant decrease of labeled Kupffer cells was present than in the inactive form of chronic hepatitis. Labeled ductular cells and fibrocytes increased as the disease progressed from acute hepatitis to liver cirrhosis. The labeling index of rosettes cells was intermediate between the hepatocytes and ductular cells. The ratio of labeled parenchymal to non-parenchymal cells decreased proportionally from chronic hepatitis to cirrhosis.

  11. Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.

    Science.gov (United States)

    Asakura, Mitsutoshi; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

    2015-04-01

    The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  12. Acute cadmium intoxication induces alpha-class glutathione S-transferase protein synthesis and enzyme activity in rat liver

    International Nuclear Information System (INIS)

    Casalino, Elisabetta; Sblano, Cesare; Calzaretti, Giovanna; Landriscina, Clemente

    2006-01-01

    Acute cadmium intoxication affects glutathione S-transferase (GST) in rat liver. It has been found that 24 h after i.p. cadmium administration to rats, at a dose of 2.5 mg CdCl 2 kg -1 body weight, the activity of this enzyme in liver cytosol increased by 40%. A less stimulatory effect persisted till 48 h and thereafter the enzyme activity normalized. Since, GST isoenzymes belong to different classes in mammalian tissues, we used quantitative immunoassays to verify which family of GST isoenzymes is influenced by this intoxication. Only alpha-class glutathione S-transferase (α-GST) proteins were detected in rat liver cytosol and their level increased by about 25%, 24 h after cadmium treatment. No pi-GST isoforms were found in liver cytosol from either normal or cadmium-treated rats. Co-administration of actinomycin D with cadmium normalized both the protein level and the activity of α-GST, suggesting that some effect occurs on enzyme transcription of these isoenzymes by this metal. On the other hand, it seems unlikely that the stimulatory effect is due to the high level of peroxides caused by lipid peroxidation, since Vitamin E administration strongly reduced the TBARS level, but did not cause any GST activity decrease

  13. Hepatoprotective effect of Solanum xanthocarpum fruit extract against CCl4 induced acute liver toxicity in experimental animals.

    Science.gov (United States)

    Gupta, Ramesh K; Hussain, Talib; Panigrahi, G; Das, Avik; Singh, Gireesh Narayan; Sweety, K; Faiyazuddin, Md; Rao, Chandana Venkateswara

    2011-12-01

    To investigate the hepatoprotective potential of Solanum xanthocarpum (Solanaceae) (S. xanthocarpum) in experimental rats to validate its traditional claim. 50% ethanolic fruit extract of S. xanthocarpum (SXE, 100, 200 or 400 mg/kg body weight) was administered daily for 14 days in experimental animals. Liver injury was induced chemically, by CCl(4) administration (1 mL/kg i. p.). The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), Serum alkaline phosphatise (SALP) and total bilirubin. Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were screened along with histopathological studies. Obtained results demonstrated that the treatment with SXE significantly (P<0.05-<0.001) and dose-dependently prevented chemically induced increase in serum levels of hepatic enzymes. Furthermore, SXE significantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and catalase towards normal levels. Histopathology of the liver tissue showed that SXE attenuated the hepatocellular necrosis and led to reduction of inflammatory cells inflltration. The results of this study strongly indicate the protective effect of SXE against acute liver injury which may be attributed to its hepatoprotective activity, and there by scientifically support its traditional use. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  14. Radioimmunoassay of human cardiac tropomyosin in acute myocardial infarction

    International Nuclear Information System (INIS)

    Cummins, P.; McGurk, B.; Littler, W.A.

    1981-01-01

    Tropomyosin was prepared from fresh human myocardium and antisera raised in rabbits. A sensitive radioimmunoassay was developed for the detection of human cardiac 125 I-labelled tropomyosin in human sera down to levels of 1 ng/ml. Values for human cardiac tropomyosin in normal patients ranged from less than 1 to 3 ng/ml. In 18 patients with acute myocardial infarction all had elevated tropomyosin levels ranging from 41 to above 200 ng/ml with a mean peak level of 101 ng/ml. In this study there were no false positive or false negative results. In the initial stages of infarction the time course of appearance and peak levels of cardiac tropomyosin, total creatine kinase and creatine kinase MB isoenzyme were similar. Although total creatine kinase and creatine kinase MB isoenzyme levels were normal after 72 h in patients with single, uncomplicated infarction, cardiac tropomyosin levels were still significantly elevated above normal after this time, being 30-60% of peak values. Radioimmunoassay of human cardiac tropomyosin may prove useful in the diagnosis and in the management of patients with acute myocardial infarction, particularly in the long-term postinfarction period. (author)

  15. Acute fatty liver of pregnancy with hypoglycaemia, diabetes insipidus and pancreatitis, preceded by intrahepatic cholestasis of pregnancy.

    Science.gov (United States)

    English, Nicola; Rao, Jegajeeva

    2015-04-15

    We present the case of a 33-year-old woman in her first pregnancy. She presented with pruritus at 34 weeks gestation. A diagnosis of intrahepatic cholestasis of pregnancy was made based on elevated bile acids and elevated liver transaminases. She re-presented 4 days later, jaundiced with abdominal pain and nausea, and was hypertensive. Her bilirubin was now elevated and her creatinine had doubled. The differential diagnosis-included pre-eclampsia and Hemolysis Elevated Liver enzymes Low Platelet count (HELLP) syndrome, and delivery was expedited. Postnatally, the patient became coagulopathic, though not thrombocytopaenic; she had persistent hypoglycaemia, hyponatraemia, developed acute pancreatitis and had profound ascites and peripheral oedema. Management was supportive with multidisciplinary care and over a period of 3 weeks she made a full clinical and biochemical recovery. 2015 BMJ Publishing Group Ltd.

  16. [Pathophysiological basis of portal hypertension and the new concept of acute kidney injury in patients with liver cirrhosis].

    Science.gov (United States)

    Wang, J B

    2017-06-20

    Recently, the International Club of Ascites (ICA) has developed a new expert consensus on the diagnosis and treatment of acute kidney injury (AKI) in patients with liver cirrhosis, which reflects the new concept of AKI management in patients with liver cirrhosis. This consensus emphasizes the increase in the absolute value of serum creatinine (SCr) and establishes a new staging system for AKI, which may help to evaluate disease progression and recovery. In addition, the new management concept also emphasizes that when AKI progresses to stage 2/3 or still progresses after comprehensive treatment, a diagnosis can be made and vasoconstrictors and albumin can be used as long as the patient meets the other diagnostic criteria for hepatorenal syndrome, regardless of SCr level.

  17. Anti-liver-kidney microsome antibody type 1 recognizes human cytochrome P450 db1.

    Science.gov (United States)

    Gueguen, M; Yamamoto, A M; Bernard, O; Alvarez, F

    1989-03-15

    Anti-liver-kidney microsome antibody type 1 (LKM1), present in the sera of a group of children with autoimmune hepatitis, was recently shown to recognize a 50 kDa protein identified as rat liver cytochromes P450 db1 and db2. High homology between these two members of the rat P450 IID subfamily and human P450 db1 suggested that anti-LKM1 antibody is directed against this human protein. To test this hypothesis, a human liver cDNA expression library in phage lambda GT-11 was screened using rat P450 db1 cDNA as a probe. Two human cDNA clones were found to be identical to human P450 db1 by restriction mapping. Immunoblot analysis using as antigen, the purified fusion protein from one of the human cDNA clones showed that only anti-LKM1 with anti-50 kDa reactivity recognized the fusion protein. This fusion protein was further used to develop an ELISA test that was shown to be specific for sera of children with this disease. These results: 1) identify the human liver antigen recognized by anti-LKM1 auto-antibodies as cytochrome P450 db1, 2) allow to speculate that mutation on the human P450 db1 gene could alter its expression in the hepatocyte and make it auto-antigenic, 3) provide a simple and specific diagnostic test for this disease.

  18. Cell Pleomorphism and Cytoskeleton Disorganization in Human Liver Cancer.

    Science.gov (United States)

    Cheng, Chiung-Chi; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Chao, Wei-Ting; Tseng, Yu-Hui; Hsu, Yung-Hsiang; Chen, You-Yin; Liu, Yi-Hsiang

    Nucleoskeleton maintains the framework of a cell nucleus that is required for a variety of nuclear functions. However, the nature of nucleoskeleton structure has not been yet clearly elucidated due to microscopy visualization limitations. Plectin, a nuclear pore-permeable component of cytoskeleton, exhibits a role of cross-linking between cytoplasmic intermediate filaments and nuclear lamins. Presumably, plectin is also a part of nucleoskeleton. Previously, we demonstrated that pleomorphism of hepatoma cells is the consequence of cytoskeletal changes mediated by plectin deficiency. In this study, we applied a variety of technologies to detect the cytoskeletons in liver cells. The images of confocal microscopy did not show the existence of plectin, intermediate filaments, microfilaments and microtubules in hepatic nuclei. However, in the isolated nuclear preparation, immunohistochemical staining revealed positive results for plectin and cytoskeletal proteins that may contribute to the contamination derived from cytoplasmic residues. Therefore, confocal microscopy provides a simple and effective technology to observe the framework of nucleoskeleton. Accordingly, we verified that cytoskeletons are not found in hepatic cell nuclei. Furthermore, the siRNA-mediated knockdown of plectin in liver cells leads to collapsed cytoskeleton, cell transformation and pleomorphic nuclei. Plectin and cytoskeletons were not detected in the nuclei of liver cells compared to the results of confocal microscopy. Despite the absence of nuclear plectin and cytoskeletal filaments, the evidence provided support that nuclear pleomorphism of cancer cells is correlated with the cytoplasmic disorganization of cytoskeleton. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  20. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    International Nuclear Information System (INIS)

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro

    2014-01-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury

  1. Modified Lipoproteins by Acrylamide Showed More Atherogenic Properties and Exposure of Acrylamide Induces Acute Hyperlipidemia and Fatty Liver Changes in Zebrafish.

    Science.gov (United States)

    Kim, Seong-Min; Baek, Ji-Mi; Lim, So-Mang; Kim, Jae-Yong; Kim, Jihoe; Choi, Inho; Cho, Kyung-Hyun

    2015-10-01

    Acrylamide is a well-known potent carcinogen and neurotoxin that, until now, has not been sufficiently investigated with regard to its effects on lipid metabolism. We investigated physiological effects of acrylamide (AA) on lipoprotein metabolism using human macrophages, dermal cells, and zebrafish models. Functional and structural properties of lipoproteins were modified by AA (final concentration of 5-100 mM) with loss of antioxidant ability and multimerization of apoA-I in vitro. AA exacerbated LDL oxidation, degradation, and LDL uptake into macrophages with increased ROS production. In human cells, treatment of AA (1-100 μM) caused cellular senescence of dermal cells with severe cytotoxicity. Waterborne exposure of zebrafish in cage water containing AA (300 ppm) resulted in acute death within 26 h along with elevation of body weight, blood glucose, triglyceride, and hepatic inflammation. AA exposure caused fat accumulation in liver in a dose-dependent manner. In conclusion, AA affected lipoprotein metabolism to result exacerbation of atherosclerosis. Exposure of zebrafish to AA resulted in acute inflammatory death with hyperlipidemia.

  2. Peak hyperammonemia and atypical acute liver failure: The eruption of an urea cycle disorder during hyperemesis gravidarum.

    Science.gov (United States)

    Weiss, Nicolas; Mochel, Fanny; Rudler, Marika; Demeret, Sophie; Lebray, Pascal; Conti, Filomena; Galanaud, Damien; Ottolenghi, Chris; Bonnefont, Jean-Paul; Dommergues, Marc; Bernuau, Jacques; Thabut, Dominique

    2017-09-20

    Inborn urea cycle disorders are under-recognised metabolic causes of hyperammonemia in adults. A 28-year-old primigravida, seven weeks pregnant, affected by hyperemesis gravidarum developed acute liver injury (ALI) and then acute liver failure (ALF) in less than 48 h. Because the patient developed atypical features, especially mildly elevated aminotransferases contrasting with very high blood ammonia levels (281 μmol/L), concomitant with normal serum creatinine, an inborn error of metabolism was suspected. We performed emergency metabolic analyses, stopped all protein intake and started with intravenous (i.v.) high caloric intake, nitrogen scavenger drugs and haemodialysis. The neurological and hepatic status of the patient quickly improved together with normalisation of her ammonemia levels. High plasma glutamine and urinary orotic acid, alongside low plasma arginine, citrulline and ornithine were suggestive of an ornithine transcarbamylase deficiency, later confirmed by molecular analyses. Foetal sex was female, as determined by foetal DNA analysis in maternal blood, and foetal development was unremarkable throughout the pregnancy. Delivery was induced at 39 weeks with a close monitoring of ammonemia levels and i.v. perfusion of carbohydrates and lipids during labour and immediately post-partum to avoid hypercatabolism. Delivery was uneventful and the patient delivered a healthy female baby. Urea cycle disorders should be contemplated in non-jaundiced patients with ALI or ALF, severe hyperammonemia and normal serum creatinine regardless of serum aminotransferase levels. The prompt recognition of this rare condition and the rapid initiation of adequate metabolic therapy are mandatory to prevent irreversible neurological sequelae and to avoid liver transplantation. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  3. Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury.

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    Yan-Ling Yang

    Full Text Available BACKGROUND: Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. METHODS: Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE. The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. RESULTS: In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. CONCLUSION: Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.

  4. An iso-α-acid-rich extract from hops (Humulus lupulus) attenuates acute alcohol-induced liver steatosis in mice.

    Science.gov (United States)

    Hege, Marianne; Jung, Finn; Sellmann, Cathrin; Jin, Chengjun; Ziegenhardt, Doreen; Hellerbrand, Claus; Bergheim, Ina

    2018-01-01

    Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-α-acids consumed in doses achieved by "normal" beer consumption have beneficial effects on health. Female C57 Bl/6 J mice, pretreated for 4 d with an iso-α-acid-rich extract (∼30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined. In the liver, acute ethanol administration led to a significant accumulation of fat (∼10-fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-α-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide. Taken together, iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Fatal Acute Liver Failure as a Consequence of Regorafenib Treatment in a Metastatic Colon Cancer

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    Dominique Béchade

    2017-08-01

    Full Text Available Regorafenib is a multikinase inhibitor which showed benefits in pretreated metastatic colorectal cancer patients. Hepatotoxicity has been described as a frequent side effect. We report the case of a 65-year-old patient presenting with jaundice, fever, and hepatocellular insufficiency which led to death of the patient. She had previously been treated with several lines of chemotherapy for sub- and diaphragmatic ganglionic metastases of a colon adenocarcinoma. There were no liver metastases. The fatal liver failure occurred at the beginning of treatment with regorafenib at a dosage of 3 tablets per day. No concomitant treatment was given, and other causes of liver damage were eliminated. The liver biopsy showed hepatocyte necrosis with lymphocyte infiltration. This observation illustrates the risk of severe hepatic involvement typically occurring within the first 2 months of treatment. Monitoring liver biology every 2 weeks is essential during the first 2 months to detect any hepatotoxicity.

  6. All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells.

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    Melanie Werner

    Full Text Available Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen.Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity.Cell preparation yielded the following cell counts per gram of liver tissue: 2.0 ± 0.4 × 10(7 hepatocytes, 1.8 ± 0.5 × 10(6 Kupffer cells, 4.3 ± 1.9 × 10(5 liver sinusoidal endothelial cells, and 3.2 ± 0.5 × 10(5 stellate cells. Hepatocytes were identified by albumin (95.5 ± 1.7% and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5 ± 1.2% and exhibited phagocytic activity, as determined with 1 μm latex beads. Endothelial cells were CD146(+ (97.8 ± 1.1% and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1 ± 1.5%. These cells further exhibited retinol (vitamin A-mediated autofluorescence.Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.

  7. Advances in diagnosis and treatment of hepatorenal syndrome type of acute kidney injury in patients with liver cirrhosis

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    SONG Tingxue

    2017-03-01

    Full Text Available Acute kidney injury (AKI is a common complication of liver cirrhosis and mainly manifests as a rapidly elevated serum creatinine level, a reduced glomerular filtration rate, and oliguria or anuria. Type 1 hepatorenal syndrome (HRS-1 is a special type of AKI, and patients with untreated HRS-1 have an extremely high risk of death. Early diagnosis and treatment are of great importance. This paper summarizes the latest diagnostic criteria for hepatorenal syndrome (HRS type of AKI and research advances in the treatment of HRS-1.

  8. Prevention and Therapeutic Effects and Mechanisms of Tanshinone IIA Sodium Sulfonate on Acute Liver Injury Mice Model

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    Lunjie Lu

    2016-01-01

    Full Text Available Tanshinone IIA sodium sulfonate (TSS is a water-soluble derivative of tanshinone IIA, which is the main pharmacologically active component of Salvia miltiorrhiza. This study aimed to verify the preventive and therapeutic effects of TSS and its combined therapeutic effects with magnesium isoglycyrrhizinate (MI in D-galactosamine- (D-Gal- induced acute liver injury (ALI in mice. The potential regulatory mechanisms of TSS on ALI were also examined. Our results may provide a basis for the development of novel therapeutics for ALI.

  9. Vascular abnormalities associated with acute hypoxia in human melanoma xenografts

    International Nuclear Information System (INIS)

    Simonsen, Trude G.; Gaustad, Jon-Vidar; Leinaas, Marit N.; Rofstad, Einar K.

    2012-01-01

    Background and purpose: The fraction of hypoxic cells has been shown to differ substantially among human tumors of the same histological type. In this study, a window chamber model was used to identify possible mechanisms leading to the development of highly different hypoxic fractions in A-07 and R-18 human melanoma xenografts. Materials and methods: Chronic and acute hypoxia was assessed in intradermal tumors using an immunohistochemical and a radiobiological assay. Functional and morphological parameters of the vascular networks of tumors growing in dorsal window chambers were assessed with intravital microscopy. Results: R-18 tumors showed significantly higher hypoxic fractions than A-07 tumors, and the difference was mostly due to acute hypoxia. Compared to A-07 tumors, R-18 tumors showed low vascular densities, low vessel diameters, long vessel segments, low blood flow velocities, frequent fluctuations in blood flow, and a high fraction of narrow vessels with absent or very low and varying flux of red blood cells. Conclusion: The high fraction of acute hypoxia in R-18 tumors was a consequence of frequent fluctuations in blood flow and red blood cell flux combined with low vascular density. The fluctuations were most likely caused by high geometric resistance to blood flow in the tumor microvasculature.

  10. Does Acute Normobaric Hypoxia Induce Anapyrexia in Adult Humans?

    Science.gov (United States)

    Seo, Yongsuk; Gerhart, Hayden D; Vaughan, Jeremiah; Kim, Jung-Hyun; Glickman, Ellen L

    2017-06-01

    Seo, Yongsuk, Hayden D. Gerhart, Jeremiah Vaughan, Jung-Hyun Kim, and Ellen L. Glickman. Does acute normobaric hypoxia induce anapyrexia in adult humans? High Alt Med Biol. 18:185-190, 2017.-Exposure to hypoxia is known to induce a reduction in core body temperature as a protective mechanism, which has been shown in both animals and humans. The purpose of this study was to test if acute exposure to normobaric hypoxia (NH) induces anapyrexia in adult humans in association with decreased peripheral oxygen saturation (SpO 2 ). Ten healthy male subjects were seated in atmospheres of normobaric normoxia 21% (NN21), NH 17% (NH17), and 13% (NH13) O 2 for 60 minutes in a counterbalanced manner. Rectal temperature (Tre) was continuously monitored together with the quantification of metabolic heat production (MHP) and body heat storage (S). Baseline physiological measurements showed no differences between the three conditions. SpO 2 was significantly decreased in NH17 and NH13 compared with NN21 (p ≤ 0.001). Tre decreased following 60 minutes of resting in all conditions, but, independent of the conditions, showed no association between Tre and levels of hypoxic SpO 2 . There was also no significant difference in either MHP or S between conditions. The present results showed no evidence of hypoxia-induced anapyrexia in adult humans during 1 hour of resting after exposure to NH either at 13% or 17% O 2 .

  11. Human Physiological Responses to Acute and Chronic Cold Exposure

    Science.gov (United States)

    Stocks, Jodie M.; Taylor, Nigel A. S.; Tipton, Michael J.; Greenleaf, John E.

    2001-01-01

    When inadequately protected humans are exposed to acute cold, excessive body heat is lost to the environment and unless heat production is increased and heat loss attenuated, body temperature will decrease. The primary physiological responses to counter the reduction in body temperature include marked cutaneous vasoconstriction and increased metabolism. These responses, and the hazards associated with such exposure, are mediated by a number of factors which contribute to heat production and loss. These include the severity and duration of the cold stimulus; exercise intensity; the magnitude of the metabolic response; and individual characteristics such as body composition, age, and gender. Chronic exposure to a cold environment, both natural and artificial, results in physiological alterations leading to adaptation. Three quite different, but not necessarily exclusive, patterns of human cold adaptation have been reported: metabolic, hypothermic, and insulative. Cold adaptation has also been associated with an habituation response, in which there is a desensitization, or damping, of the normal response to a cold stress. This review provides a comprehensive analysis of the human physiological and pathological responses to cold exposure. Particular attention is directed to the factors contributing to heat production and heat loss during acute cold stress, and the ability of humans to adapt to cold environments.

  12. Clinical features of HBV-associated acute-on-chronic liver failure induced by discontinuation of nucleoside analogues

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    LIU Xiaoyan

    2016-09-01

    Full Text Available Objective To investigate the clinical features of patients with HBV-associated acute-on-chronic liver failure (HBV-ACLF induced by the discontinuation of necleos(tide analogues. Methods A retrospective analysis was performed for 698 patients with a definite diagnosis of HBV-ACLF in The 302 Hospital of PLA from January 2014 to April 2016, and among these patients, 150 (discontinuation group had acute-on-chronic liver failure (ACLF induced by discontinuation, 396 (previously untreated group had not received antiviral therapy when they developed this disease for the first time, and the other 152 patients with ACLF caused by other reasons were enrolled as controls. The causative factors, underlying diseases, family history, serum hepatitis B markers, prognosis, and initial onset were summarized, and the drugs used and discontinuation time were recorded for patients who stopped taking necleos(tide analogues. The chi-square test was used for the comparison of categorical data between groups. Results Among the 698 patients, 355(50.86% had a family history of chronic hepatitis B (CHB, and 93 patients (62.00% in the discontinuation group had a family history of CHB. Among the 150 patients in the discontinuation group, 27 (18.00% had an underlying disease of chronic hepatitis, among whom 12 (44.44% had a family history of CHB, which was significantly lower than the overall level (χ2=2.57, P=0.07; 123 (82.00% had an underlying disease of liver cirrhosis (compensated, among whom 81 (65.85% had a family history of CHB, which was significantly higher than the overall level (χ2=48.77, P<0.001. Of all the patients in the discontinuation group, 77.33% (116/150 developed the disease within 1 year after discontinuation, and 21.33% (32/150developed the disease during the second year after discontinuation. The HBeAg-negative patients accounted for 47.33% (71/150. In the discontinuation group and previously untreated group, the patients with an underlying disease

  13. Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells

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    Fausto Nelson

    2005-12-01

    Full Text Available Abstract Alcohol abuse reduces response rates to IFN therapy in patients with chronic hepatitis C. To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes. High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines. Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway. In contrast, when combined with exogenously applied IFN-α, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation. These effects of alcohol occurred independently of i alcohol metabolism via ADH and CYP2E1, and ii cytotoxic or cytostatic effects of ethanol. In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication. Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink 12. Recombinant interferon alpha (IFN-α therapy produces sustained responses (ie clearance of viremia in 8–12% of patients with chronic hepatitis C 3. Significant improvements in response rates can be achieved with IFN plus ribavirin combination 456 and pegylated IFN plus ribavirin 78 therapies. However, over 50% of chronically infected patients still do not clear viremia. Moreover, HCV-infected patients who abuse

  14. The Acute Toxicity Test of Methanolic Extract of Hyptis pectinata Poit on Liver Balb/c Mice

    Science.gov (United States)

    Suzery, M.; Cahyono, B.; Astuti, P.

    2017-02-01

    Plants from Lamiaceae family has almost entirely reported having physiological activities. One of them is Hyptis pectinata Poit plant. Research on the toxicity of Hyptis pectinata needs to be done to protect people from the possibility of its harmful effects. This study aim to know the acute toxicity effects of Hyptis pectinata extract (HPE) on liver of Balb/c mice. This research was a laboratory experimental study using the post test only controlled group design. Balb/c mice were randomly divided into 4 groups. K (control group), P1, P2 and P3 (treatment groups; given HPE 200mg/kgBW, 1000 mg/kgBW, and 5000 mg/kgBW, respectively). The extract was orally given with gastric tube on the first day and the mice were terminated at the 8th day then the livers were observed. The Kruskal-Wallis test for macroscopic morphological and volume of the liver showed there were no significant difference with p=0.406 and p=0.054. The highest liver histopathological score was in P3 group. The Kruskal-Wallis test showed significantly difference (p=0.000). Continued with Mann-Withney test that showed a significant difference in K-P1 (p=0.009), K-P2 (p=0.009), K-P3 (p=0.009), P1-P2 (p=0.028), and P1-P3 (p=0.009). In conclusion, the HPE is safe to use which has no complication with liver of mice.

  15. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.

    Science.gov (United States)

    Gulmez, Sinem Ezgi; Larrey, Dominique; Pageaux, Georges-Philippe; Lignot, Severine; Lassalle, Régis; Jové, Jérémy; Gatta, Angelo; McCormick, P Aiden; Metselaar, Harold J; Monteiro, Estela; Thorburn, Douglas; Bernal, William; Zouboulis-Vafiadis, Irene; de Vries, Corinne; Perez-Gutthann, Susana; Sturkenboom, Miriam; Bénichou, Jacques; Montastruc, Jean-Louis; Horsmans, Yves; Salvo, Francesco; Hamoud, Fatima; Micon, Sophie; Droz-Perroteau, Cécile; Blin, Patrick; Moore, Nicholas

    2013-02-01

    Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.

  16. Identification of Pathways in Liver Repair Potentially Targeted by Secretory Proteins from Human Mesenchymal Stem Cells

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    Sandra Winkler

    2016-07-01

    Full Text Available Background: The beneficial impact of mesenchymal stem cells (MSC on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1 increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β and hypoxia-inducible factor 1-α (HIF1-α signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.

  17. Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 improves acute liver injury induced by D-galactosamine in rats.

    Science.gov (United States)

    Lv, Long-Xian; Hu, Xin-Jun; Qian, Gui-Rong; Zhang, Hua; Lu, Hai-Feng; Zheng, Bei-Wen; Jiang, Li; Li, Lan-Juan

    2014-06-01

    This work investigated the effect of the intragastric administration of five lactic acid bacteria from healthy people on acute liver failure in rats. Sprague-Dawley rats were given intragastric supplements of Lactobacillus salivarius LI01, Lactobacillus salivarius LI02, Lactobacillus paracasei LI03, Lactobacillus plantarum LI04, or Pediococcus pentosaceus LI05 for 8 days. Acute liver injury was induced on the eighth day by intraperitoneal injection of 1.1 g/kg body weight D-galactosamine (D-GalN). After 24 h, samples were collected to determine the level of liver enzymes, liver function, histology of the terminal ileum and liver, serum levels of inflammatory cytokines, bacterial translocation, and composition of the gut microbiome. The results indicated that pretreatment with L. salivarius LI01 or P. pentosaceus LI05 significantly reduced elevated alanine aminotransferase and aspartate aminotransferase levels, prevented the increase in total bilirubin, reduced the histological abnormalities of both the liver and the terminal ileum, decreased bacterial translocation, increased the serum level of interleukin 10 and/or interferon-γ, and resulted in a cecal microbiome that differed from that of the liver injury control. Pretreatment with L. plantarum LI04 or L. salivarius LI02 demonstrated no significant effects during this process, and pretreatment with L. paracasei LI03 aggravated liver injury. To the best of our knowledge, the effects of the three species-L. paracasei, L. salivarius, and P. pentosaceus-on D-GalN-induced liver injury have not been previously studied. The excellent characteristics of L. salivarius LI01 and P. pentosaceus LI05 enable them to serve as potential probiotics in the prevention or treatment of acute liver failure.

  18. Rapid Evolution from the First Episode of Acute Pancreatitis to Chronic Pancreatitis in Human Subjects

    OpenAIRE

    Elie Aoun; Adam Slivka; Dionysios J Papachristou; David C Whitcomb; Ferga C Gleeson; Georgios I Papachristou

    2007-01-01

    Context Growing evidence suggests that recurrent acute pancreatitis leads to chronic pancreatitis, but this sequence is seldom reported in human subjects. The sentinel acute pancreatitis event hypothesis suggests that an initial episode of acute pancreatitis is the first step in a complicated series of events ultimately leading to chronic pancreatitis. Objective To identify patients who evolved from recurrent acute pancreatitis to chronic pancreatitis. Setting The Severity of Acute Pancreatit...

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

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    Kazushige Nirei

    2013-01-01

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

  20. Lansoprazole-induced acute lung and liver injury: a case report.

    Science.gov (United States)

    Atkins, Christopher; Maheswaran, Tina; Rushbrook, Simon; Kamath, Ajay

    2014-12-01

    A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.

  1. The acute effect of cannabis on plasma, liver and brain ammonia dynamics, a translational study.

    Science.gov (United States)

    Abulseoud, Osama A; Zuccoli, Maria Laura; Zhang, Lifeng; Barnes, Allan; Huestis, Marilyn A; Lin, Da-Ting

    2017-07-01

    Recent reports of ammonia released during cannabis smoking raise concerns about putative neurotoxic effects. Cannabis (54mg) was administered in a double-blind, placebo-controlled design to healthy cannabis users (n=15) either orally, or through smoking (6.9%THC cigarette) or inhalation of vaporized cannabis (Volcano®). Serial assay of plasma ammonia concentrations at 0, 2, 4, 6, 8, 10, 15, 30, and 90min from onset of cannabis administration showed significant time (P=0.016), and treatment (P=0.0004) effects with robust differences between placebo and edible at 30 (P=0.002), and 90min (P=0.007) and between placebo and vaporized (P=0.02) and smoking routes (P=0.01) at 90min. Furthermore, plasma ammonia positively correlated with blood THC concentrations (P=0.03). To test the hypothesis that this delayed increase in plasma ammonia originates from the brain we administered THC (3 and 10mg/kg) to mice and measured plasma, liver, and brain ammonia concentrations at 1, 3, 5 and 30min post-injection. Administration of THC to mice did not cause significant change in plasma ammonia concentrations within the first 5min, but significantly reduced striatal glutamine-synthetase (GS) activity (P=0.046) and increased striatal ammonia concentration (P=0.016). Furthermore, plasma THC correlated positively with striatal ammonia concentration (Pcannabis intake caused time and route-dependent increases in plasma ammonia concentrations in human cannabis users and reduced brain GS activity and increased brain and plasma ammonia concentrations in mice. Published by Elsevier B.V.

  2. Temporal Changes in Rat Liver Gene Expression after Acute Cadmium and Chromium Exposure

    Science.gov (United States)

    2015-05-19

    g). Hydroxyl radical measurements Electron spin resonance (ESR) spin trapping was used to detect short-lived free radical inter- mediates. Flash ...Grand Island, NY) from samples of liver tissue flash frozen in liquid N2, followed by purification with an RNeasy Mini Kit (Qiagen, Liver Gene...Tripartite motif 24 (Trim24/Tif1alpha) tumor suppressor protein is a novel negative regulator of interferon (IFN)/signal transducers and activators of

  3. Effect of ultrasound frequency on the Nakagami statistics of human liver tissues.

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    Po-Hsiang Tsui

    Full Text Available The analysis of the backscattered statistics using the Nakagami parameter is an emerging ultrasound technique for assessing hepatic steatosis and fibrosis. Previous studies indicated that the echo amplitude distribution of a normal liver follows the Rayleigh distribution (the Nakagami parameter m is close to 1. However, using different frequencies may change the backscattered statistics of normal livers. This study explored the frequency dependence of the backscattered statistics in human livers and then discussed the sources of ultrasound scattering in the liver. A total of 30 healthy participants were enrolled to undergo a standard care ultrasound examination on the liver, which is a natural model containing diffuse and coherent scatterers. The liver of each volunteer was scanned from the right intercostal view to obtain image raw data at different central frequencies ranging from 2 to 3.5 MHz. Phantoms with diffuse scatterers only were also made to perform ultrasound scanning using the same protocol for comparisons with clinical data. The Nakagami parameter-frequency correlation was evaluated using Pearson correlation analysis. The median and interquartile range of the Nakagami parameter obtained from livers was 1.00 (0.98-1.05 for 2 MHz, 0.93 (0.89-0.98 for 2.3 MHz, 0.87 (0.84-0.92 for 2.5 MHz, 0.82 (0.77-0.88 for 3.3 MHz, and 0.81 (0.76-0.88 for 3.5 MHz. The Nakagami parameter decreased with the increasing central frequency (r = -0.67, p < 0.0001. However, the effect of ultrasound frequency on the statistical distribution of the backscattered envelopes was not found in the phantom results (r = -0.147, p = 0.0727. The current results demonstrated that the backscattered statistics of normal livers is frequency-dependent. Moreover, the coherent scatterers may be the primary factor to dominate the frequency dependence of the backscattered statistics in a liver.

  4. Hepatoprotective effect of Opuntia dillenii seed oil on CCl4 induced acute liver damage in rat

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    Mohamed Bouhrim

    2018-01-01

    Full Text Available Objective: To investigate the hepatoprotective effect of Opuntia dillenii seed oil (ODSO on CCl4 provoked liver injury in rat. Methods: Animals were treated orally with ODSO at a concentration of 2 mL/kg, once daily for one week before the first intraperitoneal injection of CCl4, and thereafter the administration of the oil was continued for 7 days until the introduction of the second injection of CCl4. Fourteen hours after the last dose of CCl4, rats were sacrificed, and the relative liver weight, weight gain, alkaline phosphatase, aspartate amino transferase, alanine aminotransferase, direct bilirubin, total bilirubin, triglycerides, total cholesterol, very low density lipoprotein, low density lipoprotein, high density lipoprotein, plasmatic glucose, urea, creatinine, acid uric and malondialdehyde were determined. Results: The significant increase was found in relative liver weight and plasma levels of alanine aminotransferase, aspartate amino transferase, alkaline phosphatase, total bilirubin, direct bilirubin, triglycerides, very low-density lipoprotein, urea, uric acid and malondialdehyde. Likewise, the significant decrease was indicated in the weight gain and the level of glucose plasmatic, and high-density lipoprotein levels in CCl4 produced liver injury in rats were re-established to normal levels when treated with ODSO. While, no change was observed in the total cholesterol, low-density lipoprotein and creatinine in all animals. Conclusions: We conclude that the ODSO has a protective effect on CCl4-mediated liver injury. Hence, we suggest its inclusion as a preventive control of liver disorders.

  5. Acute Liver Failure in a Patient Travelling From Asia: The Other Face of the Coin of Infectious Disease.

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    Abdulrahman, Balen; Ahmed, Mohamed H; Ramage, John

    2017-08-01

    We present a case of a 63-year-old male who had travelled from South India to United Kingdom (UK) visiting relatives. He had developed episodes of diarrhea, vomiting and fevers while travelling and on assessment in hospital, mild abdominal distension was noted with rapid deterioration to hypovolemic shock. Initial blood test showed a low platelet count with deranged liver function tests (LFTs). It was noted that during admission to intensive care unit (ICU), blood continued to ooze from a previous surgical laparoscopy wound, central and arterial line access sites. Blood results revealed ongoing derangement of clotting and LFT. Computed tomography (CT) scan showed possible acute cholecystitis and a laparoscopy showed an ischemic-looking liver and gut but no significant gallbladder abnormality. The virology screen was positive for dengue virus antibodies IgM and IgG. The patient developed multi-organ failure and deteriorated despite intensive support. Post mortem showed fulminant hepatic failure and acute tubular necrosis of kidneys.

  6. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

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    Amanda Natália Lucchesi

    2015-01-01

    Full Text Available Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC and 30 untreated diabetic (UD rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

  7. The Use of an Acellular Oxygen Carrier in a Human Liver Model of Normothermic Machine Perfusion.

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    Laing, Richard W; Bhogal, Ricky H; Wallace, Lorraine; Boteon, Yuri; Neil, Desley A H; Smith, Amanda; Stephenson, Barney T F; Schlegel, Andrea; Hübscher, Stefan G; Mirza, Darius F; Afford, Simon C; Mergental, Hynek

    2017-11-01

    Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L. Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury. The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species, and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure. Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid.

  8. Proton MR spectroscopic features of the human liver: in-vivo application to the normal condition

    International Nuclear Information System (INIS)

    Cho, Soon Gu; Kim, Mi Young; Kim, Young Soo; Choi, Won; Shin, Seok Hwan; Ok, Chul Soo; Suh, Chang Hae

    1999-01-01

    To determine the feasibility of MR spectroscopy in the living human liver, and to evaluate the corresponding proton MR spectroscopic features. In fifteen normal volunteers with neither previous nor present liver disease, the proton MR spectroscopic findings were reviewed. Twelve subjects were male and three were female ; they were aged between 28 and 32 (mean, 30) years. MR spectroscopy involved the use of a 1.5T GE Signa Horizon system with body coil(GE Medical System, Milwaukee, U.S.A). We used STEAM (Stimulated Echo-Acquisition Mode) with 3000/30 msec of TR/TE for signal acquisition, and the prone position without respiratory interruption. Mean and standard deviation of the ratios of glutamate+glutamine/lipids, phosphomonoesters/lipids, and glycogen+glucose/lipids were calculated from the area of their peaks. The proton MR spectroscopic findings of normal human livers showed four distinctive peaks, i.e. lipids, glutamate and glutamine complex, phosphomonoesters, and glycogen and glucose complex. The mean and standard deviation of the ratios of glutamate+glutamine/lipids, phosphomonoesters/lipids, and glycogen+glucose/lipids were 0.02±0.01, 0.01±0.01, and 0.04±0.03, respectively. In living normal human livers, MR spectroscopy can be successfully applied. When applied to a liver whose condition is pathologic, the findings can be used as a standard

  9. Human Liver Cells Expressing Albumin and Mesenchymal Characteristics Give Rise to Insulin-Producing Cells

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    Irit Meivar-Levy

    2011-01-01

    Full Text Available Activation of the pancreatic lineage in the liver has been suggested as a potential autologous cell replacement therapy for diabetic patients. Transcription factors-induced liver-to-pancreas reprogramming has been demonstrated in numerous species both in vivo and in vitro. However, human-derived liver cells capable of acquiring the alternate pancreatic repertoire have never been characterized. It is yet unknown whether hepatic-like stem cells or rather adult liver cells give rise to insulin-producing cells. Using an in vitro experimental system, we demonstrate that proliferating adherent human liver cells acquire mesenchymal-like characteristics and a considerable level of cellular plasticity. However, using a lineage-tracing approach, we demonstrate that insulin-producing cells are primarily generated in cells enriched for adult hepatic markers that coexpress both albumin and mesenchymal markers. Taken together, our data suggest that adult human hepatic tissue retains a substantial level of developmental plasticity, which could be exploited in regenerative medicine approaches.

  10. Red Sea Suberea mollis Sponge Extract Protects against CCl4-Induced Acute Liver Injury in Rats via an Antioxidant Mechanism

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    Aymn T. Abbas

    2014-01-01

    Full Text Available Recent studies have demonstrated that marine sponges and their active constituents exhibited several potential medical applications. This study aimed to evaluate the possible hepatoprotective role as well as the antioxidant effect of the Red Sea Suberea mollis sponge extract (SMSE on carbon tetrachloride- (CCl4- induced acute liver injury in rats. In vitro antioxidant activity of SMSE was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH assay. Rats were orally administered three different concentrations (100, 200, and 400 mg/kg of SMSE and silymarin (100 mg/kg along with CCl4 (1 mL/kg, i.p., every 72 hr for 14 days. Plasma aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP, and total bilirubin were measured. Hepatic malondialdehyde (MDA, reduced glutathione (GSH, nitric oxide (NO, superoxide dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT were also measured. Liver specimens were histopathologically examined. SMSE showed strong scavenging activity against free radicals in DPPH assay. SMSE significantly reduced liver enzyme activities. Moreover, SMSE significantly reduced hepatic MDA formation. In addition, SMSE restored GSH, NO, SOD, GPx, and CAT. The histopathological results confirmed these findings. The results of this study suggested a potent protective effect of the SMSE against CCl4-induced hepatic injury. This may be due to its antioxidant and radical scavenging activity.

  11. Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

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    Kamran Qureshi

    2014-01-01

    Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

  12. Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini

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    Gasser Robin B

    2007-06-01

    Full Text Available Abstract Background Cholangiocarcinoma (CCA – cancer of the bile ducts – is associated with chronic infection with the liver fluke, Opisthorchis viverrini. Despite being the only eukaryote that is designated as a 'class I carcinogen' by the International Agency for Research on Cancer, little is known about its genome. Results Approximately 5,000 randomly selected cDNAs from the adult stage of O. viverrini were characterized and accounted for 1,932 contigs, representing ~14% of the entire transcriptome, and, presently, the largest sequence dataset for any species of liver fluke. Twenty percent of contigs were assigned GO classifications. Abundantly represented protein families included those involved in physiological functions that are essential to parasitism, such as anaerobic respiration, reproduction, detoxification, surface maintenance and feeding. GO assignments were well conserved in relation to other parasitic flukes, however, some categories were over-represented in O. viverrini, such as structural and motor proteins. An assessment of evolutionary relationships showed that O. viverrini was more similar to other parasitic (Clonorchis sinensis and Schistosoma japonicum than to free-living (Schmidtea mediterranea flatworms, and 105 sequences had close homologues in both parasitic species but not in S. mediterranea. A total of 164 O. viverrini contigs contained ORFs with signal sequences, many of which were platyhelminth-specific. Examples of convergent evolution between host and parasite secreted/membrane proteins were identified as were homologues of vaccine antigens from other helminths. Finally, ORFs representing secreted proteins with known roles in tumorigenesis were identified, and these might play roles in the pathogenesis of O. viverrini-induced CCA. Conclusion This gene discovery effort for O. viverrini should expedite molecular studies of cholangiocarcinogenesis and accelerate research focused on developing new interventions

  13. Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver.

    Science.gov (United States)

    Nencini, Cristina; Franchi, Gian Gabriele; Cavallo, Federica; Micheli, Lucia

    2010-04-01

    This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury.

  14. Acute liver failure during treatment of interferon alpha 2a chronic hepatitis B and coinfection of parvovirus B19

    Science.gov (United States)

    Sobala-Szczygieł, Barbara; Boroń-Kaczmarska, Anna; Kępa, Lucjan; Oczko-Grzesik, Barbara; Piotrowski, Damian; Stolarz, Wojciech

    Parvovirus B19 infection is associated with a broad spectrum of clinical manifestations among which some are well known but others remain controversial. The role of this infection as a cause of acute hepatitis or exacerbation of chronic liver disease requires discussion regarding its significance in a strategy of prevention and treatment of patients with chronic hepatitis. Clinical importance of this infection in patients with chronic hepatitis B treated with pegylated interferon alpha 2a is still unclear but exactly in this population significant complications during treatment may arise. Parvovirus B19 infection is not rare among persons with chronic hepatitis B, therefore searching for co-infection should be placed in standard diagnostic procedures especially in case of exacerbation of chronic hepatitis, pancytopaenia or anaemia of unknown origin. Pegylated interferon alpha 2a still remains a gold standard of therapy of patients with chronic hepatitis B according to European (EASL) and Polish guidelines. We present a case of 35 years old woman treated with pegylated interferon alpha 2a who developed acute liver failure in 23rd week of chronic hepatitis B therapy. An exacerbation of hepatitis with encephalopathy and pancytopaenia have been observed. Parvovirus B19 and HBV co-infection does not increase the frequency of liver function abnormalities in patients with chronic hepatitis B. Further investigations should be done to describe the natural course of co-infection with parvovirus B19 and HBV and to establish possible association between parvovirus B19 infection and chronic hepatitis B and also the influence of interferon alpha 2a on the infections course.

  15. Human bocavirus in children with acute respiratory infections in Vietnam.

    Science.gov (United States)

    Tran, Dinh Nguyen; Nguyen, Tran Quynh Nhu; Nguyen, Tuan Anh; Hayakawa, Satoshi; Mizuguchi, Masashi; Ushijima, Hiroshi

    2014-06-01

    Acute respiratory infections are the major cause of morbidity and mortality globally. Human bocavirus (HBoV), a novel virus, is recognized to increasingly associate with previously unknown etiology respiratory infections in young children. In this study, the epidemiological, clinical, and molecular characteristics of HBoV infections were described in hospitalized Vietnamese pediatric patients. From April 2010 to May 2011, 1,082 nasopharyngeal swab samples were obtained from patients with acute respiratory infections at the Children's Hospital 2, Ho Chi Minh City, Vietnam. Samples were screened for HBoV by PCR and further molecularly characterized by sequencing. HBoV was found in 78 (7.2%) children. Co-infection with other viruses was observed in 66.7% of patients infected with HBoV. Children 12-24 months old were the most affected age group. Infections with HBoV were found year-round, though most cases occurred in the dry season (December-April). HBoV was possible to cause severe diseases as determined by higher rates of hypoxia, pneumonia, and longer hospitalization duration in patients with HBoV infection than in those without (P-value infection with HBoV did not affect the disease severity. The phylogenetic analysis of partial VP1 gene showed minor variations and all HBoV sequences belonged to species 1 (HBoV1). In conclusion, HBoV1 was circulating in Vietnam and detected frequently in young children during dry season. Acute respiratory infections caused by HBoV1 were severe enough for hospitalization, which implied that HBoV1 may have an important role in acute respiratory infections among children. © 2013 Wiley Periodicals, Inc.

  16. Rearrangement of a common cellular DNA domain on chromosome 4 in human primary liver tumors

    International Nuclear Information System (INIS)

    Pasquinelli, C.; Garreau, F.; Bougueleret, L.; Cariani, E.; Thiers, V.; Croissant, O.; Hadchouel, M.; Tiollais, P.; Brechot, C.; Grzeschik, K.H.

    1988-01-01

    Hepatitis B virus (HBV) DNA integration has been shown to occur frequently in human hepatocellular carcinomas. The authors have investigated whether common cellular DNA domains might be rearranged, possibly by HBV integration, in human primary liver tumors. Unique cellular DNA sequences adjacent to an HBV integration site were isolated from a patient with hepatitis B surface antigen-positive hepatocellular carcinoma. These probes detected rearrangement of this cellular region of chromosomal DNA in 3 of 50 additional primary liver tumors studied. Of these three tumor samples, two contained HBV DNA, without an apparent link between the viral DNA and the rearranged allele; HBV DNA sequences were not detected in the third tumor sample. By use of a panel of somatic cell hybrids, these unique cellular DNA sequences were shown to be located on chromosome 4. Therefore, this region of chromosomal DNA might be implicated in the formation of different tumors at one step of liver cell transformation, possible related to HBV integration

  17. A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

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    Roxanne Lim

    2014-01-01

    Full Text Available Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM, Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.

  18. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

    Science.gov (United States)

    Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

    2017-07-01

    The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

  19. Biology and relevance of human acute myeloid leukemia stem cells.

    Science.gov (United States)

    Thomas, Daniel; Majeti, Ravindra

    2017-03-23

    Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly 2 decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse and implies that approaches to treatment must eradicate LSCs for cure. More recently, a number of studies have both refined and expanded our understanding of LSCs and intrapatient heterogeneity in AML using improved xenotransplant models, genome-scale analyses, and experimental manipulation of primary patient cells. Here, we review these studies with a focus on the immunophenotype, biological properties, epigenetics, genetics, and clinical associations of human AML LSCs and discuss critical questions that need to be addressed in future research. © 2017 by The American Society of Hematology.

  20. Targeted immunotherapy in acute myeloblastic leukemia: from animals to humans.

    Science.gov (United States)

    Robin, Marie; Schlageter, Marie-Hélène; Chomienne, Christine; Padua, Rose-Ann

    2005-10-01

    Immunity against acute myeloid leukemia (AML) is demonstrated in humans by the graft-versus-leukemia effect in allogeneic hematopoietic stem cell transplantation. Specific leukemic antigens have progressively been discovered and circulating specific T lymphocytes against Wilms tumor antigen, proteinase peptide or fusion-proteins produced from aberrant oncogenic chromosomal translocations have been detected in leukemic patients. However, due to the fact that leukemic blasts develop various escape mechanisms, antileukemic specific immunity is not able to control leukemic cell proliferation. The aim of immunotherapy is to overcome tolerance and boost immunity to elicit an efficient immune response against leukemia. We review different immunotherapy strategies tested in preclinical animal models of AML and the human trials that spurred from encouraging results obtained in animal models, demonstrate the feasibility of immunotherapy in AML patients.

  1. Suppression of Human Liver Cancer Cell Migration and Invasion via the GABAA Receptor

    International Nuclear Information System (INIS)

    Chen, Zhi-ao; Bao, Mei-yan; Xu, Yong-fen; Zha, Ruo-peng; Shi, Hai-bing; Chen, Tao-yang; He, Xiang-huo

    2012-01-01

    To investigate the roles of the γ-aminobutyric acid (GABA) in the metastasis of hepatocellular carcinoma (HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC. The expression levels of GABA receptor subunit genes in various HCC cell lines and patients‘ tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Transwell cell migration and invasion assays were carried out for functional analysis. The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer. The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue. GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABA A receptor as a result of the induction of liver cancer cell cytoskeletal reorganization. Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo. These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system

  2. MRI-based assessment of liver perfusion and hepatocyte injury in the murine model of acute hepatitis.

    Science.gov (United States)

    Byk, Katarzyna; Jasinski, Krzysztof; Bartel, Zaneta; Jasztal, Agnieszka; Sitek, Barbara; Tomanek, Boguslaw; Chlopicki, Stefan; Skorka, Tomasz

    2016-12-01

    To assess alterations in perfusion and liver function in the concanavalin A (ConA)-induced mouse model of acute liver failure (ALF) using two magnetic resonance imaging (MRI)-based methods: dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA contrast agent and arterial spin labelling (ASL). BALB/c mice were studied using a 9.4 T MRI system. The IntraGateFLASH TM and FAIR-EPI pulse sequences were used for optimum mouse abdomen imaging. The average perfusion values for the liver of the control and ConA group were equal to 245 ± 20 and 200 ± 32 ml/min/100 g (p = 0.008, respectively). DCE-MRI showed that the time to the peak of the image enhancement was 6.14 ± 1.07 min and 9.72 ± 1.69 min in the control and ConA group (p < 0.001, respectively), while the rate of the contrast wash-out in the control and ConA group was 0.037 ± 0.008 and 0.021 ± 0.008 min -1 (p = 0.004, respectively). These results were consistent with hepatocyte injury in the ConA-treated mice as confirmed by histopathological staining. Both the ASL and DCE-MRI techniques represent a reliable methodology to assess alterations in liver perfusion and hepatocyte integrity in murine hepatitis.

  3. Lipopolysaccharide precipitates hepatic encephalopathy and increases blood-brain barrier permeability in mice with acute liver failure.

    Science.gov (United States)

    Chastre, Anne; Bélanger, Mireille; Nguyen, Bich N; Butterworth, Roger F

    2014-03-01

    Acute liver failure (ALF) is frequently complicated by infection leading to precipitation of central nervous system complications such as hepatic encephalopathy (HE) and increased mortality. There is evidence to suggest that when infection occurs in ALF patients, the resulting pro-inflammatory mechanisms may be amplified that could, in turn, have a major impact on blood-brain barrier (BBB) function. The aim of this study was to investigate the role of endotoxemia on the progression of encephalopathy in relation to BBB permeability during ALF. Adult male C57-BL6 mice with ALF resulting from azoxymethane-induced toxic liver injury were administered trace amounts of the endotoxin component lipopolysaccharide (LPS). Effects on the magnitude of the systemic inflammatory response, liver pathology and BBB integrity were measured as a function of progression of HE, defined as time to loss of corneal reflex (coma). Lipopolysaccharide caused additional two- to seven-fold (P liver pathology and associated increases of circulating transaminases as well as increased hyperammonaemia consistent with a further loss of viable hepatocytes. LPS treatment of ALF mice led to a rapid precipitation of hepatic coma and the BBB became permeable to the 25-kDa protein immunoglobulin G (IgG). This extravasation of IgG was accompanied by ignificant up-regulation of matrix metalloproteinase-9 (MMP-9), an endopeptidase known to modulate opening of the BBB in a wide range of neurological disorders. These findings represent the first direct evidence of inflammation-related BBB permeability changes in ALF. © 2013 John Wiley & Sons A/S. Publishing by John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Human rhinovirus infection in young African children with acute wheezing

    Directory of Open Access Journals (Sweden)

    Zar Heather J

    2011-03-01

    Full Text Available Abstract Background Infections caused by human rhinoviruses (HRVs are important triggers of wheezing in young children. Wheezy illness has increasingly been recognised as an important cause of morbidity in African children, but there is little information on the contribution of HRV to this. The aim of this study was to determine the role of HRV as a cause of acute wheezing in South African children. Methods Two hundred and twenty children presenting consecutively at a tertiary children's hospital with a wheezing illness from May 2004 to November 2005 were prospectively enrolled. A nasal swab was taken and reverse transcription PCR used to screen the samples for HRV. The presence of human metapneumovirus, human bocavirus and human coronavirus-NL63 was assessed in all samples using PCR-based assays. A general shell vial culture using a pool of monoclonal antibodies was used to detect other common respiratory viruses on 26% of samples. Phylogenetic analysis to determine circulating HRV species was performed on a portion of HRV-positive samples. Categorical characteristics were analysed using Fisher's Exact test. Results HRV was detected in 128 (58.2% of children, most (72% of whom were under 2 years of age. Presenting symptoms between the HRV-positive and negative groups were similar. Most illness was managed with ambulatory therapy, but 45 (35% were hospitalized for treatment and 3 (2% were admitted to intensive care. There were no in-hospital deaths. All 3 species of HRV were detected with HRV-C being the most common (52% followed by HRV-A (37% and HRV-B (11%. Infection with other respiratory viruses occurred in 20/128 (16% of HRV-positive children and in 26/92 (28% of HRV-negative samples. Conclusion HRV may be the commonest viral infection in young South African children with acute wheezing. Infection is associated with mild or moderate clinical disease.

  6. Differential genomic effects of six different TiO2 nanomaterials on human liver HepG2 cells

    Science.gov (United States)

    Engineered nanoparticles are reported to cause liver toxicity in vivo. To better assess the mechanism of the in vivo liver toxicity, we used the human hepatocarcinoma cells (HepG2) as a model system. Human HepG2 cells were exposed to 6 TiO2 nanomaterials (with dry primary partic...

  7. Fatal veno-occlusive disease of the liver after chemotherapy, whole-body irradiation and bone marrow transplantation for refractory acute leukaemia

    International Nuclear Information System (INIS)

    Jacobs, P.; Miller, J.L.; Uys, C.J.; Dietrich, B.E.

    1979-01-01

    Rapid onset of liver failure with fatal outcome occured in a young woman after successful bone marrow transplantation undertaken for refractory acute leukaemia. Centrilobular necrosis was demonstrated at autopsy and was attributed to prior cytotoxic chemotherapy, possibly potentiated by the total-body irradiation that was used in preparation for the transplant. This association between liver damage and prolonged drug therapy, coupled with the short median survival currently achieved within these chemotherapy regimens, has initiated an evaluation of bone marrow transplantation in patients with leukaemia during the first complete remission, rather than at a later stage when cumulative drug toxicity to the liver may have taken place

  8. Acute effects of organotins on brain, liver and kidney in rats

    Energy Technology Data Exchange (ETDEWEB)

    Dwivedi, R.S.; Kaur, G.; Srivastava, R.C.; Srivastava, T.N.

    1985-01-01

    Effects of dioctyltin oxide (DOTO) tricyclohexyltin hydroxide (TCHTOH) and tributyltin oxide (TBTO) were examined on some enzymic activities in liver and kidney and biogenic amines level in brain of rats at 24 hours after single subcutaneous administration (25 ..mu..mole/100 g B. Wt.). All the organotin compounds produced a significant increase in the activity of alkaline phosphatase and adenosin triphosphatase and decrease in monoamine oxidase in both liver and kidney. DOTO and TCHTOH were more effective in impairing the activity of succinate dehydrogenase in liver. Concentrations of ..gamma..-aminobutyric acid (GABA) and dopamine were found to be significantly decreased in brain however, acetylcholine concentration remained unaltered. These results suggest that organotin compounds DOTO and TCHTOH are more toxic to rats than TBTO. 30 references, 3 tables.

  9. Chlamydia pneumoniae acute liver infection affects hepatic cholesterol and triglyceride metabolism in mice.

    Science.gov (United States)

    Marangoni, Antonella; Fiorino, Erika; Gilardi, Federica; Aldini, Rita; Scotti, Elena; Nardini, Paola; Foschi, Claudio; Donati, Manuela; Montagnani, Marco; Cevenini, Monica; Franco, Placido; Roda, Aldo; Crestani, Maurizio; Cevenini, Roberto

    2015-08-01

    Chlamydia pneumoniae has been linked to atherosclerosis, strictly associated with hyperlipidemia. The liver plays a central role in the regulation of lipid metabolism. Since in animal models C. pneumoniae can be found at hepatic level, this study aims to elucidate whether C. pneumoniae infection accelerates atherosclerosis by affecting lipid metabolism. Thirty Balb/c mice were challenged intra-peritoneally with C. pneumoniae elementary bodies and thirty with Chlamydia trachomatis, serovar D. Thirty mice were injected with sucrose-phosphate-glutamate buffer, as negative controls. Seven days after infection, liver samples were examined both for presence of chlamydia and expression of genes involved in inflammation and lipid metabolism. C. pneumoniae was isolated from 26 liver homogenates, whereas C. trachomatis was never re-cultivated (P triglycerides levels compared both with negative controls (P metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Detection of titanium particles in human liver and spleen and possible health implications

    NARCIS (Netherlands)

    Heringa, M.B.; Peters, R.J.B.; Bleys, R.L.A.W.; Lee, van der M.K.; Tromp, P.C.; Kesteren, van P.C.E.; Eijkeren, van J.C.H.; Undas, A.K.; Oomen, A.G.; Bouwmeester, H.

    2018-01-01

    Background: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal

  11. Microsomal UDP-glucuronyltransferase-catalyzed bilirubin diglucuronide formation in human liver

    NARCIS (Netherlands)

    Peters, W. H.; Jansen, P. L.

    1986-01-01

    Human liver microsomal bilirubin UDP-glucuronyltransferase catalyzes formation of bilirubin mono- and diglucuronide. KmUDPGA and Vmax of the enzyme are 0.6 mM and 1.69 nmol/mg protein X min. In vitro, bilirubin readily dissolves in the microsomal lipid phase. Taking this into account a Kmbilirubin

  12. Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

    DEFF Research Database (Denmark)

    Khamri, Wafa; Abeles, Robin D; Hou, Tie Zheng

    2017-01-01

    , hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood...... mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF......BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86...

  13. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

    Directory of Open Access Journals (Sweden)

    Erkko Ylösmäki

    Full Text Available MicroRNAs (miRNAs are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5 in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.

  14. The draft genome of the carcinogenic human liver fluke Clonorchis sinensis

    Science.gov (United States)

    2011-01-01

    Background Clonorchis sinensis is a carcinogenic human liver fluke that is widespread in Asian countries. Increasing infection rates of this neglected tropical disease are leading to negative economic and public health consequences in affected regions. Experimental and epidemiological studies have shown a strong association between the incidence of cholangiocarcinoma and the infection rate of C. sinensis. To aid research into this organism, we have sequenced its genome. Results We combined de novo sequencing with computational techniques to provide new information about the biology of this liver fluke. The assembled genome has a total size of 516 Mb with a scaffold N50 length of 42 kb. Approximately 16,000 reliable protein-coding gene models were predicted. Genes for the complete pathways for glycolysis, the Krebs cycle and fatty acid metabolism were found, but key genes involved in fatty acid biosynthesis are missing from the genome, reflecting the parasitic lifestyle of a liver fluke that receives lipids from the bile of its host. We also identified pathogenic molecules that may contribute to liver fluke-induced hepatobiliary diseases. Large proteins such as multifunctional secreted proteases and tegumental proteins were identified as potential targets for the development of drugs and vaccines. Conclusions This study provides valuable genomic information about the human liver fluke C. sinensis and adds to our knowledge on the biology of the parasite. The draft genome will serve as a platform to develop new strategies for parasite control. PMID:22023798

  15. Uneven acute non-alcoholic fatty change of the liver after percutaneous transhepatic portal vein embolization in a patient with hilar cholangiocarcinoma - a case report.

    Science.gov (United States)

    Tsai, Chun-Yi; Nojiri, Motoi; Yokoyama, Yukihiro; Ebata, Tomoki; Mizuno, Takashi; Nagino, Masato

    2017-12-06

    Portal vein embolization is essential for patients with biliary cancer who undergo extended hepatectomy to induce hypertrophy of the future remnant liver. Over 830 patients have undergone the portal vein embolization at our institution since 1990. Non-alcoholic fatty liver disease is an entity of hepatic disease characterized by fat deposition in hepatocytes. It has a higher prevalence among persons with morbid obesity, type 2 diabetes, and hyperlipidemia. Neither the mechanism of hepatic hypertrophy after portal vein embolization nor the pathophysiology of non-alcoholic fatty liver disease has been fully elucidated. Some researchers integrated the evident insults leading to progression of fatty liver disease into the multiple-hit hypothesis. Among these recognized insults, the change of hemodynamic status of the liver was never mentioned. We present the case of a woman with perihilar cholangiocarcinoma who received endoscopic biliary drainage and presented to our institute for surgical consultation. A left trisectionectomy with caudate lobectomy and extrahepatic bile duct resection was indicated for curative treatment. To safely undergo left trisectionectomy, she underwent selective portal vein embolization of the liver, in which uneven acute fatty change subsequently developed. The undrained left medial sector of the liver with dilated biliary tracts was spared the fatty change. The patient underwent planned surgery without any major complications 6 weeks after the event and has since resumed a normal life. The discrepancies in fatty deposition in the different sectors of the liver were confirmed by pathologic interpretations. This is the first report of acute fatty change of the liver after portal vein embolization. The sparing of the undrained medial sector is unique and extraordinary. The images and pathologic interpretations presented in this report may inspire further research on how the change of hepatic total inflow after portal vein embolization can be

  16. Prognostic factors of the short-term outcomes of patients with hepatitis B virus-associated acute-on-chronic liver failure.

    Science.gov (United States)

    Lei, Qing; Ao, Kangjian; Zhang, Yinhua; Ma, Deqiang; Ding, Deping; Ke, Changzheng; Chen, Yue; Luo, Jie; Meng, Zhongji

    2017-11-01

    To investigate the impact of the baseline status of patients with hepatitis B virus-associated acute-on-chronic liver failure on short-term outcomes. A retrospective study was conducted that included a total of 138 patients with hepatitis B virus-associated acute-on-chronic liver failure admitted to the Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, from November 2013 to October 2016. The patients were divided into a poor prognosis group (74 patients) and a good prognosis group (64 patients) based on the disease outcome. General information, clinical indicators and prognostic scores of the patients' baseline status were analyzed, and a prediction model was established accordingly. Elder age, treatment with artificial liver support systems and the frequency of such treatments, high levels of white blood cells, neutrophils, neutrophil count/lymphocyte count ratio, alanine aminotransferase, gamma-glutamyl transferase, total bilirubin, urea, and prognostic scores as well as low levels of albumin and sodium were all significantly associated with the short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure. The predictive model showed that logit (p) = 3.068 + 1.003 × neutrophil count/lymphocyte count ratio - 0.892 × gamma-glutamyl transferase - 1.138 × albumin - 1.364 × sodium + 1.651 × artificial liver support therapy. The neutrophil count/lymphocyte count ratio and serum levels of gamma-glutamyl transferase, albumin and sodium were independent risk factors predicting short-term outcomes of hepatitis B virus-associated acute-on-chronic liver failure, and the administration of multiple treatments with artificial liver support therapy during the early stage is conducive to improved short-term outcomes.

  17. Radioimmunoassay of human cardiac tropomyosin in acute myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Cummins, P; McGurk, B; Littler, W A [Queen Elizabeth Hospital, Birmingham (UK)

    1981-03-01

    Tropomyosin was prepared from fresh human myocardium and antisera raised in rabbits. A sensitive radioimmunoassay was developed for the detection of human cardiac /sup 125/I-labelled tropomyosin in human sera down to levels of 1 ng/ml. Values for human cardiac tropomyosin in normal patients ranged from less than 1 to 3 ng/ml. In 18 patients with acute myocardial infarction all had elevated tropomyosin levels ranging from 41 to above 200 ng/ml with a mean peak level of 101 ng/ml. In this study there were no false positive or false negative results. In the initial stages of infarction the time course of appearance and peak levels of cardiac tropomyosin, total creatine kinase and creatine kinase MB isoenzyme were similar. Although total creatine kinase and creatine kinase MB isoenzyme levels were normal after 72 h in patients with single, uncomplicated infarction, cardiac tropomyosin levels were still significantly elevated above normal after this time, being 30-60% of peak valuctional hourly rate of absorption and the plasma /sup 32/P radioactivity at 60 min corrected for extracellular fluid volume provided the best app elements, the characteristics of which are determined by employing the Lagrange multiplier concept. Unknowns of the resulting simultaneous equation consist of usual nodal displacements of the whole stru element codes. Therefore, FAST should be useful in several areas for which all other codes are too unwieldy and expensivnt makers was established, in which the investigations and studies have started.

  18. Toxicidad hepática recurrente secundaria a metilprednisolona intravenosa Recurrent acute liver toxicity from intravenous methyprednisolone

    Directory of Open Access Journals (Sweden)

    M. Rivero Fernández

    2008-11-01

    Full Text Available Las reacciones adversas hepáticas relacionadas con la administración de fármacos (hepatotoxicidad son cuadros relativamente frecuentes que presentan una amplia variabilidad clínica e histológica. La identificación precoz de estos cuadros es fundamental en la práctica clínica debido a su potencial gravedad. En la mayoría de los casos la suspensión del fármaco desencadenante es suficiente para la resolución del cuadro clínico. A pesar de que los esteroides son utilizados en una amplia variedad de situaciones clínicas, la notificación de cuadros de hepatotoxicidad secundaria a esteroides intravenosos es excepcional. Presentamos el caso clínico de una mujer diagnosticada de esclerosis múltiple, que recibió metilprednisolona a altas dosis en forma de "pulsos" intravenosos como tratamiento de las reagudizaciones de su enfermedad y pre