Treatment Of Acute Hepatic Failure Research Articles

Diosmetin exerts anti-oxidative, anti-inflammatory and anti-apoptotic effects to protect against endotoxin-induced acute hepatic failure in mice.

To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN). In vitro, diosmetin scavenged free radicals. In vivo, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. In addition, diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice. The underlying mechanisms are antioxidation, NF-κB signaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression. Diosmetin is thus a potential drug candidate for use in the treatment of acute hepatic failure.

Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

Effect of bone marrow mesenchymal stem cell transplantation on acute hepatic failure in rats.

The aim of the present study was to investigate the effectiveness of bone marrow mesenchymal stem cell (BMSC) transplantation in the treatment of acute hepatic failure (AHF) in rats. BMSCs were isolated from rat bone marrow, cultured and analyzed by flow cytometry. Following BMSC transplantation into rats with AHF, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), direct bilirubin (DBIL) and indirect bilirubin (IBIL) in the serum were measured using an automatic biochemical analyzer. Hematoxylin and eosin (H&E) staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed to analyze the pathological changes and apoptosis rate. Levels of cluster of differentiation (CD)163 and interleukin (IL)-10 in the serum and liver tissue were detected by an enzyme-linked immunosorbent assay (ELISA) assay and western blot analysis. Compared with the levels in the control group, the serum levels of ALT, AST, DBIL, IBIL, CD163 and IL-10 in the BMSC transplantation groups were significantly lower at 120 and 168 h, while the serum levels of ALB were significantly higher at 168 h after BMSC transplantation. The pathological features of liver failure were alleviated by BMSC transplantation. The expression levels of CD163 and IL-10 in the liver tissue were also significantly decreased following transplantation. The results indicate that BMSCs have a therapeutic effect on AHF in rats, and CD163 and IL-10 may be used as sensitive serum prognosis indicators in the early assessment of patients following liver transplantation.

Reduction of Acute Hepatic Damage Induced by Acetaminophen after Treatment with Diphenyl Diselenide in Mice

In this study, the authors evaluated the ability of diphenyl diselenide (PhSe)(2) to reverse acute hepatic failure induced by acetaminophen (APAP) in mice. The animals received an APAP dose of 600 mg/kg intraperitoneally (i.p.), and then 1 hour later, they received 15.6 mg/kg i.p. of (PhSe)(2). Three hours after (PhSe)(2) administration, the animals were sacrificed and blood and liver samples were collected for analysis. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG), thiobarbituric acid-reactive substances (TBARS), 2',7'-dichlorofluorescein (DFC), catalase activity (CAT), and myeloperoxidase (MPO) activity were determined in the liver. A methyl-tetrazolium reduction (MTT) assay was also performed on the liver. Histopathological studies were conducted in all groups. Exposure of animals to APAP induced oxidative stress, increased lipid peroxidation (LPO), and the generation of reactive species, reduced the levels of GSH, and caused an increase in the MPO activity. Treatment with (PhSe)(2) reduced LPO and the formation of reactive species and inhibited the processes of inflammation, reducing the hepatic damage induced by APAP. The results of this study show that (PhSe)(2) is a promising therapeutic option for the treatment of acute hepatic failure.

Treatment of Acute Hepatic Failure in Mice by Transplantation of Mixed Microencapsulation of Rat Hepatocytes and Transgenic Human Fetal Liver Stromal Cells

Microencapsulation-mediated cell therapy overcomes the immune incompatibility between donor and recipient in transplantation. The aim of this study was to investigate the effects of transplantation of microcapsules containing a mixture of rat hepatocytes and human fetal liver stromal cells (hFLSCs), engineered to produce basic fibroblast growth factor (bFGF), on acute liver failure (ALF) in mice. In vitro experiments showed that different combinations of microencapsulated rat's hepatocytes and stromal cells survive, grow, and function better in three-dimensional conditions. The metabolic activity of rat hepatocytes co-microencapsulated with hFLSCs, particularly when engineered to produce bFGF (FLSCs/bFGF), is significantly higher than that of microcapsules with rat hepatocytes alone. Intraperitoneal transplantation of the encapsulated hepatocytes with FLSCs/bFGF increased the survival rate and improved liver function of an ALF mouse model induced by a 70% partial hepatectomy in BALB/C mice. Moreover, dramatic liver regeneration was observed 2 days after transplantation in the group that received intraperitoneal transplantations of encapsulated hepatocytes with FLSCs/bFGF. Therefore, transplantation of encapsulated hepatocytes and hFLSCs/bFGF may be a promising strategy to treat ALF or related liver diseases.

Study on the transplantation of microencapsulated hepatic-like cells derived from umbilical cord blood cells for the treatment of acute hepatic failure in rats

Study on the transplantation of microencapsulated hepatic-like cells derived from umbilical cord blood cells for the treatment of acute hepatic failure in rats

Impaired Hepatocyte Regeneration in Acute Severe Hepatic Injury Enhances Effective Repopulation by Transplanted Hepatocytes

Efficient repopulation by transplanted hepatocytes in the severely injured liver is essential for their clinical application in the treatment of acute hepatic failure. We studied here whether and how the transplanted hepatocytes are able to efficiently repopulate the toxin-induced acute injured liver. Male dipeptidyl peptidase IV-deficient F344 rats were randomized to receive retrorsine plus D-galactosamine (R+D-gal) treatment or D-galactosamine-alone (D-gal) to induce acute hepatic injury, and retrorsine-alone. In these models, retrorsine was used to inhibit the proliferation of endogenous hepatocytes while D-galactosamine induced acute hepatocyte damage. Wild-type hepatocytes (1 x 10(7)/ml) were transplanted intraportally 24 h after D-galactosamine or saline injection. The kinetics of proliferation and repopulation of transplanted cells and the kinetics of cytokine response, hepatic stellate cell (HSC) activation, and matrix metalloproteinase (MMP2) expression were analyzed. We observed that early entry of transplanted hepatocytes into the hepatic plates and massive repopulation of the liver by transplanted hepatocytes occurred in acute hepatic injury induced by R+D-gal treatment but not by D-gal-alone or retrorsine-alone. The expressions of transforming growth factor-alpha and hepatocyte growth factor genes in the R+D-gal injured liver were significantly upregulated and prolonged up to 4 weeks after hepatocyte transplantation. The expression kinetics were parallel with the efficient proliferation and repopulation of transplanted hepatocytes. HSC was activated rapidly, markedly, and prolongedly up to 4 weeks after hepatocyte transplantation, when the expression of HGF gene and repopulation of transplanted hepatocytes were reduced afterward. Furthermore, the expression kinetics of MMP2 and its specific distribution in the host areas surrounding the expanding clusters of transplanted hepatocytes are consistent with those of activated HSC. Impaired hepatocyte regeneration after acute severe hepatic injury may initiate serial compensatory repair mechanisms that facilitate the extensive repopulation by transplanted hepatocytes that enter early the hepatic plates.

Use of Plasmapheresis in Acute Hepatic Failure Due to Hepatitis a

Purpose: Plasmapheresis, or plasma exchange, is the removal of whole blood, then replacement of only plasma and return of the new plasma as well as the other blood components to the patient. The goal is to remove large molecular weight substances that reside in the plasma and cause various diseases. These substances include: pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxin, and cholesterol containing lipoproteins. Plasma exchange is considered to be standard therapy for diseases such as: polyneuropathies, Goodpature's Syndrome, thrombotic thrombocytopenic purpura (TTP), myasthenia gravis, and Guillain-Barre Syndrome. There is not sufficient evidence to use plasmapheresis in acute hepatic failure, although there have been some studies that show benefit. We report a case of successful use of plasmapheresis in acute hepatic failure due to Hepatitis A. Methods: A 25 year-old female with history of GERD presented with diffuse abdominal pain, nausea, vomiting, and jaundice, after returning from a trip to India. Laboratory data was significant for transaminitis, hyperbilirubinemia, and coagulopathy secondary to Hepatitis A. The patient was transferred to The University Hospital for fulminant hepatic failure and evaluation for liver transplant. Both liver function and mental status rapidly worsened over 4 days. Because of the decline in clinical status, the patient was listed for a liver transplant. In light of the lifelong immunosuppression and possible need for re-transplant, the team decided on plasmapheresis before attempting transplant. Results: After one plasma exchange, symptoms, clinical status, and liver function tests markedly improved. Patient no longer needed transplantation and to this day remains asymptomatic with normalized liver function. Conclusion: Plasmapheresis is not considered to be the standard of care in the treatment of acute hepatic failure. There are several studies performed outside of the United States reporting patients with hepatic failure that improved with plasmapheresis. However, these studies have small patient numbers and show improvement in coagulopathy, not neurologic status or complete recovery of liver function. There has been a study on the use of plasma exchange in children with acute hepatic failure, most of which were due to congenital causes. We report what we believe is the only case of successful use of plasmapheresis with full recovery after fulminant hepatic failure secondary to Hepatitis A in an adult.

Stimulated Bile Production and Outflow in the Prevention and Treatment of Acute Hepatic Failure

Objective. To employ bile stimulation as a method for preventing and treating acute hepatic failure. Materials and methods. The results of the clinical examination and treatment of 52 inpatients treated for obstructive jaundice-complicated cholelithiasis, by stimulating bile production and outflow. Results. All the patients with acute hepatic failure underwent 48 endoscopic interventions (endoscopic papillosphincterotomy) and 4 choledochotomy, followed by stimulation of bile production and outflow. Enhanced bile production and outflow with adequate bile outflow into the duodenum completely evacuated gallstones from the biliary tract into the duodenum and normalized the composition of hepatic bile, which could, as a rule, get clear of the signs of hepatic failure completely within 10—12 days. Conclusion. The actual possibility exists of treating and preventing acute hepatic failure, by stimulating bile production and outflow in patients with obstructive jaundice-complicated cholelithiasis. Open-access surgery (laparotomy, choledochotomy, external choledochal drainage) is indicated when endoscopic drainage of the bilious tree is ineffective and when the clinical manifestations of hepatic failure increase in cholelithiasis.

A model which can be used to improve the treatment of acute hepatic failure.

Abstract A model using the pig from wich the liver has been removed for isolated perfusion, as a subject showing some of the features of acute hepatic failure for later treatment by cross-circulation with its own perfused liver, is desceribed. Effects of such a procedure on such a procedure on the glucose and halothane metabolism and intravascular coagulation and bleeding are detailed.

A bioartificial liver support system using primary hepatocytes: a preclinical study in a new porcine hepatectomy model

BackgroundBioartificial liver support systems providing a bridge to transplantation or even a definitive treatment of acute hepatic failure are a current focus of research. Different devices are used, although an impact on patient survival is doubtful for the time being. After developing a new flat membrane bioreactor, further preclinical studies have become necessary. Existing animal models of fulminant hepatic failure show common difficulties in defining a reproducible loss of functional liver tissue while considering systemic side effects. We now present a reproducible model with total hepatectomy in pigs, suitable to test the safety and efficacy of liver support systems. MethodsTwelve pigs underwent total hepatectomy by using silicone tubes and a Y-adapter as vascular prosthesis; intracranial pressure was measured via a subdural probe. Anhepatic pigs were monitored under general anesthesia until death occurred. All were treated with a new flat membrane bioreactor (FMB) that contained porcine hepatocytes in 6 of the 12 cases. ResultsOur hepatectomy technique proved to be successful without requiring venovenous bypass circulation. Mean vascular clamping time was 9 minutes. The mean survival time was longer in animals treated with hepatocyte-equipped bioreactors than in untreated animals (24.8 ± 4.3 vs 16.4 ± 4.7 hours), which already showed increased intracranial pressure after 10 to 12 hours. Serum albumin levels indicated stable cell-specific functions of the FMB. ConclusionsThe described technique of total hepatectomy is a well-reproducible animal model. The presented FMB maintained stable cell-specific functions and is a safe and efficient device.

A novel bioartificial liver containing small tissue fragments: efficiency in the treatment of acute hepatic failure induced by carbon tetrachloride in rats.

The efficiency of a new bioartificial liver (BAL) containing small tissue fragments in the treatment of acute hepatic failure induced by carbon tetrachloride in rats was evaluated. A day after injection (i.p.) of CCl4 the animals were connected to a BAL containing liver fragments (fragment BAL) and a BAL containing no liver fragments (no-fragment BAL), and extracorporeal hemoperfusion was carried out for 4 h. The activities of alanine transaminase and lactate dehydrogenase as well as the concentrations of ammonia, glucose, urea, and amino acids in plasma were measured. A tendency to the stabilisation of ammonia, glucose, phenylalanine, tyrosine, and other amino acids was revealed at the end of hemoperfusion in poisoned rats connected to the fragment BAL. A statistically significant difference in survival between the animals connected to the fragment BAL and no-fragment BAL was found. The results obtained indicate that the bioreactor containing small liver fragments is effective in the treatment of acute hepatic failure in animals.

Concept for modular extracorporeal liver support for the treatment of acute hepatic failure.

Acute liver failure has a poor prognosis. The introduction of liver transplantation as a therapeutic option reduced mortality to 20-40%.With the growing disparity between the number of organ donations and the number of patients waiting for liver transplantation, efforts have been made to optimize the allocation of organs and to design extracorporeal methods to support the failing liver. The modular extracorporeal liver support is a concept for the treatment of hepatic failure. The CellModule is a multicompartment bioreactor for extracorporeal liver support therapy. The construction provides efficient integrated oxygenator functions and decentralized mass transfer is effected by a woven array of capillary systems. The bioreactor promotes primary human liver cells to spontaneous neo-formation of liver sinusoidal structures in vitro. Small capillary subunits, in which interwoven membrane links represent the liver lobuli, are simultaneously perfused. The used cell mass of 400-600 g enabled the clinical application of a liver lobe equivalent hybrid organ. The DetoxModule enables albumin-dialysis for removal of albumin-bound toxins; a DialysisModule for continuous veno-venous hemofiltration can be added to the system, in the case of hepato-renal failure.

Artificial liver support - "bridge to transplantation?"

Over the last 40 years, the treatment of acute hepatic failure (AHF) has developed rapidly, leading to a reduction in morbidity and mortality. Part of this reduction is attributable to marked improvements in the specialist medical management of these patients, but advances in surgical techniques and pharmaceutical treatments have resulted in successful liver transplant programs being established, significantly improving mortality. However, the success of transplantation programs isdependent upon organ availability and retrieval, and many patients are either unsuitable for transplantation or die before a suitable donor is found. In order to further reduce morbidity and mortality, alternatives techniques to support the failing liver have been explored. This review examines the clinical impact of the techniques that have been used to provide extracorporeal hepatic support. Non-biological, biological and hybrid support are discussed, offering a comprehensive historical overview and an appraisal of current and...

Animal models of acute hepatic failure.

The understanding and treatment of acute hepatic failure has developed rapidly over the last 40 years reducing morbidity and mortality from this syndrome. Progress has been made by the study of animal models that reflect the clinical, biochemical and histological pattern of the syndrome seen in man. This is of increasing importance with the use of therapeutic intervention, liver transplantation and the use of extra-corporeal liver support devices. This review examines and critically appraises the various approaches to the study of acute hepatic failure in animal models, including both surgical and pharmacological approaches.

Review article: liver support systems in acute hepatic failure.

The treatment of acute hepatic failure has developed rapidly over the last 40 years, reducing morbidity and mortality from this syndrome. Whilst this has been partly attributed to significant improvements in the specialist medical management of these patients, advances in surgical techniques and pharmaceutical developments have led to the establishment of successful liver transplantation programmes, which have improved mortality significantly. This review will examine the clinical impact of alternative methods that have been used to provide extra-corporeal hepatic support. Non-biological, bio- logical and hybrid hepatic extra-corporeal support will be explored, offering a comprehensive historical overview and an appraisal of present and future advances.

Treatment of acute hepatic failure and encephalopathy with extracorporeal ex vivo pig-liver perfusion in the critical care unit

Treatment of acute hepatic failure and encephalopathy with extracorporeal ex vivo pig-liver perfusion in the critical care unit

Cytotoxicity of bile in human Hep G2 cells and in primary cultures of rat hepatocytes.

There has been increasing interest in the development of a hepatocyte bioreactor for the treatment of acute hepatic failure; however, little is known about the effect of hepatocyte byproducts on the viability of the cells in the bioreactor environment. We investigated the effects of increasing concentrations of bile on the growth and viability of the human hepatoma cell line Hep G2 and on the cytochrome P-450 content and dependent mixed function oxidase (MFO) activities, reduced glutathione (GSH) content, and glutathione S-transferase (GST) activity of primary cultures of rat hepatocytes. Our purpose was to determine whether or not it would be necessary to pretreat the plasma from patients with acute liver failure to remove elevated bile concentrations which might be toxic to the hepatocytes in an artificial liver device. Bile was found to inhibit Hep G2 cell growth at concentrations as low as 0.1% and to decrease viability at concentrations above 0.5%. The cytochrome P-450 and GSH contents and the activities of the MFO system and of GST were decreased in the primary cultures of hepatocytes following 24 h treatment with concentrations of bile at and above 0.5%. The MFO activities associated with different cytochrome P-450 isoenzymes decreased to different extents in the presence of bile with the O-dealkylation of pentoxyresorufin being more labile than that of ethoxyresorufin. Our data indicate that elevated bile concentrations are cytotoxic to liver cells, and it may be necessary to pretreat patient plasma to decrease its bile content to protect the cells during the clinical operation of a hepatocyte bioreactor device.

Polymeric membranes for hybrid liver support devices: the effect of membrane surface wettability on hepatocyte viability and functions.

Extracorporeal therapies based on membrane hybrid liver support devices using primary hepatocytes are an interesting approach to the treatment of acute hepatic failure. In such devices, semipermeable polymeric membranes are effectively used as immunoselective barriers between a patient's blood and the xenocytes in order to prevent the immune rejection of the graft. The membranes may act also as the substratum for cell adhesion, thus favouring the viability and functions of anchorage-dependent cells such as the hepatocytes. Membrane cytocompatibility is expected to depend on the surface properties of the polymer, such as its morphology and its physico-chemical properties. In this paper, we report our investigation on the effect of the surface wettability of membranes on hepatocyte viability and functions. Polypropylene microporous membranes were modified to increase their surface wettability and were used as substrata for rat hepatocyte adhesion culture. Isolated hepatocytes were also cultured on collagen as a reference substratum. Hepatocyte viability generally improved as the cells were cultured on more wettable membranes. In agreement with the viability data, the increasing wettability of the membrane surface also improved some metabolic functions.

Hemodiabsorption in Treatment of Acute Hepatic Failure and Chronic Cirrhosis with Ascites

Hemodiabsorption is a selective chemical removal process during which blood passes through dialysis membrane packages surrounded by a suspension of fine sorbent particles. The BioLogic-DT system contains charcoal and cation exchangers in a suspension that passes through dialysate spaces of a cellulosic membrane plate dialyzer. The system has proven effective in treatment of patients with serious drug overdose and has demonstrated positive effects in treatment of stage 4 coma due to hepatic failure. Recently, the charcoal in this system has been preloaded with branch chain amino acids to return these acids to patients while aromatic amino acids are removed. Further improvements include addition of osmotically active agents to the priming fluid and sorbent to increase blood oncotic pressure and transfer of ascitic fluid to blood while ultrafiltration transfers fluid out of the blood. Clinical testing of these improvements is now beginning in patients with ascites and encephalopathy due to chronic hepatic insufficiency and cirrhosis. Future improvements will include protein permeable membranes to increase removal of protein-bound toxins and addition of hepatic cells downstream from the hemodiabsorption unit.