Protective effects of oxymatrine against lipopolysaccharide/D­galactosamine­induced acute liver failure through oxidative damage, via activation of Nrf2/HO­1 and modulation of inflammatory TLR4­signaling pathways.

Oxymatrine has a variety of pharmacological functions, including anti-viral, anti-liver fibrotic, anti-cancer, anti­bacterial, anti­epidemic, analgesic, anti­allergy and anti­inflammatory properties. The present study aimed to investigate the protective effects of oxymatrine against lipopolysaccharide (LPS)/D­galactosamine (D­GalN)­induced acute liver failure and the associated underlying mechanisms. Mice were administrated 4 mg/kg LPS and 600 mg/kg D­GalN. Then, mice in the Oxymatrine group were treated with 120 mg/kg of oxymatrine for 4 weeks. Oxymatrine treatment increased survival rate, decreased plasma aspartate transaminase and alanine aminotransferase activity, increased superoxide dismutase and glutathione peroxidase and decreased malondialdehyde, tumor necrosis factor­ and myeloperoxidase activities in mice with LPS/D­GalN­induced liver failure. Furthermore, Oxymatrine activated nuclear factor erythroid 2­related factor (Nrf) 2 and heme oxygenase (HO)­1 protein expression, and suppressed Toll like receptor (TLR)4, myeloid differentiation primary response 88 and nuclear factor­κB protein expression in mice LPS/D­GalN mice. Overall, the present study suggests that oxymatrine effectively attenuates LPS/D­GalN­induced acute liver failure by oxidative damage via activation of Nrf2/HO­1 and modulation of TLR4­dependent inflammatory signaling pathways.

Rescue case of low birth weight infant with acute hepatic failure.

We report a case involving a rescued low birth weight infant (LBWI) with acute liver failure. CASE: The patient was 1594 g and 323/7 gestational wk at birth. At the age of 11 d, she developed acute liver failure due to gestational alloimmune liver disease. Exchange transfusion and high-dose gamma globulin therapy were initiated, and body weight increased with enteral nutrition. Exchange transfusion was performed a total of 33 times prior to living donor liver transplantation (LDLT). Her liver dysfunction could not be treated by medications alone. At 55 d old and a body weight of 2946 g, she underwent LDLT using an S2 monosegment graft from her mother. Three years have passed with no reports of intellectual disability or liver dysfunction. LBWIs with acute liver failure may be rescued by LDLT after body weight has increased to over 2500 g.

Hepatoprotective Effects of Kaempferol-3-O-α-l-Arabinopyranosyl-7-O-α-l-Rhamnopyranoside on d-Galactosamine and Lipopolysaccharide Caused Hepatic Failure in Mice.

Fulminant hepatic failure (FHF), associated with high mortality, is characterized by extensive death of hepatocytes and hepatic dysfunction. There is no effective treatment for FHF. Several studies have indicated that flavonoids can protect the liver from different factor-induced injury. Previously, we found that the extracts of Elaeagnus mollis leaves had favorable protective effects on acute liver injury. However, the role and mechanisms behind that was elusive. This study examined the hepatoprotective mechanisms of kaempferol-3-O-α-l-arabinopyranosyl-7-O-α-l-rhamnopyra-noside (KAR), a major flavonol glycoside of E. mollis, against d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. KAR reduces the mouse mortality, protects the normal liver structure, inhibits the serum aspartate aminotransferase (AST) and alamine aminotransferase (ALT) activity and decreases the production of malondialdehyde (MDA) and reactive oxygen species (ROS) and inflammatory cytokines, TNF-α, IL-6, and IL-1ß. Furthermore, KAR inhibits the apoptosis of hepatocytes and reduces the expression of TLR4 and NF-κB signaling pathway-related proteins induced by GalN/LPS treatment. These findings suggest that the anti-oxidative, anti-inflammatory, and anti-apoptotic effects of KAR on GalN/LPS-induced acute liver injury were performed through down-regulating the activity of the TLR4 and NF-κB signaling pathways.

Effectiveness of Fractionated Plasma Separation and Absorption as a Treatment for Amanita Phalloides Poisoning.

BACKGROUND Fractionated plasma separation and absorption (FPSA) is an extracorporeal liver support method that detoxifies accumulated toxins. There are limited data of its use in the treatment of Amanita phalloides intoxication. The objective of this study was to investigate whether FPSA before liver transplantation improves patients' short-term post liver transplantation survival in Amanita phalloides poisoning. MATERIAL AND METHODS The study population consisted of ten patients who had liver transplantation (LT) due to acute liver failure (ALF) caused by Amanita phalloides poisoning. Six patients were treated with FPSA before liver transplantation. All the patients who were started on FPSA were also placed on the liver transplantation list according to emergent liver transplantation criteria. RESULTS Patients treated with FPSA were in a more severe clinical condition presenting in higher mean MELD, total bilirubin, INR and ammonia along with more frequent hypoglycemia and hepatic encephalopathy grade 3/4. FPSA group had longer mean waiting time on the recipient list (3.5 vs. 1.25 days) but inferior thirty-day survival rate (16.5% vs. 100%). CONCLUSIONS When conservative medical modalities are ineffective, the only treatment for Amanita phalloides poisoning is a liver transplant. Although FPSA treated patients had inferior post-LT survival, FPSA was found to prolong the pre surgical waiting time for critically ill patients, consequently giving a chance of life-saving procedure.

Clinical Features and Outcomes of Complementary and Alternative Medicine Induced Acute Liver Failure and Injury.

OBJECTIVES: The increasing use of complementary and alternative medicines (CAMs) has been associated with a rising incidence of CAM-induced drug-induced liver injury (DILI). The aim of this study was to examine the clinical features and outcomes among patients with acute liver failure (ALF) and acute liver injury (ALI) enrolled in the Acute Liver Failure Study Group database, comparing CAM-induced with prescription medicine (PM)-induced DILI. METHODS: A total of 2,626 hospitalized patients with ALF/ALI of any etiology were prospectively enrolled between 1998 and 2015 from 32 academic transplant centers. Only those with CAM or PM-induced ALI/ALF were selected for analysis. RESULTS: A total of 253 (9.6%) subjects were found to have idiosyncratic DILI, of which 41 (16.3%) were from CAM and 210 (83.7%) were due to PM. The fraction of DILI-ALF/ALI cases due to CAM increased from 1998-2007 to 2007-2015 (12.4 vs. 21.1%, P=0.047). There was no difference in the type of liver injury-hepatocellular, cholestatic, or mixed-between groups as determined by R score (P=0.26). PM-induced DILI showed higher serum alkaline phosphatase levels compared with the CAM group (median IU/L, 171 vs. 125, P=0.003). The CAM population had fewer comorbid conditions (1.0 vs. 2.0, P<0.005), higher transplantation rates (56 vs. 32%, P<0.005), and a lower ALF-specific 21-day transplant-free survival (17 vs. 34%, P=0.044). CONCLUSIONS: CAM-induced DILI is at least as severe in presentation as that observed due to PM with higher rates of transplantation and lower transplant-free survival in those who progress to ALF. This study highlights the increasing incidence of CAM-induced liver injury and emphasizes the importance of early referral and evaluation for liver transplantation when CAM-induced liver injury is suspected.

Improved prescription of taohechengqi-tang alleviates D-galactosamine acute liver failure in rats.

AIM: To investigate the hepatoprotective effect of improved prescription of Taohechengqi-tang (IPTT) against acute liver failure (ALF) in rats. METHODS: Seventy specific pathogen free male Wistar rats were randomly divided into four groups: control group (normal rats, n = 10), ALF group (ALF model, n = 20), Stronger Neo-Minophagen C (SNMC) group (ALF model + SNMC, n = 20), and IPTT group (ALF model + IPTT, n = 20). The ALF model group was administered an intraperitoneal injection of D-galactosamine (1.4 g/kg), and the control group received normal saline intraperitoneally. The SNMC and IPTT groups were treated with SMMC (15.6 mg/kg) or IPTT (28.6 g/kg) by gavage at 24 h intervals, and the ALF and control groups were treated with normal saline. At 36 h after injection, serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, and cholinesterase and prothrombin time were determined, and liver histopathological scores were observed by microscopy after hematoxylin and eosin staining. mRNA expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) and caspase-3 were analyzed via fluorescence quantitative reverse transcriptase polymerase chain reaction. Proliferating cell nuclear antigen (PCNA) immunohistochemistry in liver tissue was also performed. RESULTS: D-galactosamine notably decreased the biochemical and coagulation profiles in serum. IPTT not only improved liver function and histopathology but also normalized the gene expression levels in liver tissue. Compared with the model group, in the IPTT and SNMC groups, HMGB1 mRNA/ß-actin (0.06 ± 0.03, 0.11 ± 0.04 vs 0.25 ± 0.04, P < 0.05); TLR4 mRNA/ß-actin (0.07 ± 0.02, 0.22 ± 0.08 vs 0.41 ± 0.22, P < 0.05); NF-κB mRNA/ß-actin (0.74 ± 0.41, 1.78 ± 0.64 vs 2.68 ± 1.35, P < 0.05); and caspase-3 mRNA/ß-actin levels were all significantly reduced (1.61 ± 0.45, 2.57 ± 1.04 vs 3.41 ± 0.85, P < 0.05). The gene expression levels were significantly lower in the IPTT group than in the SNMC group (P < 0.05). Compared with the model group, the PCNA expression in liver tissue was significantly enhanced in the IPTT and SNMC groups (36.34 ± 4.91, 25.57 ± 2.94 vs 17.55 ± 2.40, P < 0.05). CONCLUSION: IPTT attenuates inflammation in ALF via inhibition of HMGB1 production, which may contribute to limited liver regeneration.

Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.

The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.

Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: a case report.

Neonatal hemochromatosis (NH) is a rare and severe liver disease of mainly intra-uterine onset, characterized by neonatal liver failure, hepatic and extrahepatic iron accumulation. This leads to an altered iron metabolism with resulting siderosis. The disease represents the most common cause of liver failure in neonates and is also the most common indication for neonatal liver transplantation. We present a case of a newborn diagnosed with NH and life threatening liver failure. Initial treatment consisted of chelation therapy and antioxidants, but lack of laboratory and clinical improvement led to an exchange transfusion followed by the singular substitution of intravenous immunoglobulin (IVIG). Both, exchange transfusion and IVIG were tolerated well and led to an improvement of the general condition of the patient and recovery of liver synthetic function. The subsequent favorable course of the disease is described in this case report.

Treatment of Amanita phalloides intoxication by fractionated plasma separation and adsorption (Prometheus®).

OBJECTIVE: To investigate the effectiveness and safety of extracorporeal detoxification using the fractionated plasma separation and adsorption system (FPSA, Prometheus® 4008H, Fresenius Medical Care, Germany) in patients suffering from acute liver failure due to intoxication with Amanita phalloides (AP) toxin. METHODS: The study population consisted of 20 patients with proven AP intoxication (FPSA treatment group n=9, control group n=11). Urinary amanitin toxin concentration was measured by the Amanitin ELISA Kit (Bühlmann Laboratories, Germany, cut off level 1.5 ng/ml). All patients received standard medical treatment with activated charcoal, i.v. crystalloid fluids, silibinine and N-acetylcysteine. Additionally 9 patients underwent treatment with FPSA until undetectable amanitin levels. RESULTS: Mean urinary amanitin levels were significantly reduced by FPSA with 42.5 +/- 21.9 ng/ml before and 1.2 +/- 0.31 ng/ml after treatment (p=0.04). No hemodynamic, respiratory or hematological complications were observed. None of the patients had to undergo liver transplantation. All patients in the treatment group survived and were discharged fully recovered. One patient in the control group died due to shock and lactic acidosis; one patient remained dialysis dependent. Mean duration of hospital stay was 7.1 days in the treatment group and 11.7 days in the control group (p=0.30). CONCLUSIONS: Use of liver support therapy by fractionated plasma separation and adsorption (Prometheus®) offers a safe way for elimination of Amanita toxin with the potential to avoid the need for liver transplantation.

Effect of fulminant hepatic failure porcine plasma supplemented with essential components on encapsulated rat hepatocyte spheroids.

The development of bioartificial liver (BAL) systems has required detailed information about the functional capabilities of cultured hepatocytes during blood or plasma passage. In this study we investigated the effects of porcine plasma and various supplements on the viability and function of adult rat hepatocytes in vitro. Primary rat hepatocytes cultured in porcine plasma supplemented with various substances showed albumin synthesis rates and viability equal to or higher than those of controls. Supplementation with calcium chloride, magnesium sulfate, trace elements, amino acids, insulin, and epidermal growth factor were essential to maintain viability and high albumin synthesis. Especially, trace elements showed significantly higher and longer albumin secretion. Isolated rat hepatocytes were cultured in Spinner flasks for 24 hours to form spheroids that were harvested and encapsulated with chitosan-alginate solution before transfer to the bioreactor in the BAL system. Encapsulated rat hepatocyte spheroids cultured with porcine plasma including trace elements showed higher viability (57%) than controls (40%) after 24 hours, with ammonia removal values of 30.92 µg/10(6) cells versus the control 9.04 µg/10(6) cells. After 24 hours of operation the urea secretion value of encapsulated rat hepatocyte spheroids cultured in porcine plasma in the presence versus absence of trace elements was 76.73 µg/10(6) cells and 18.80 µg/10(6) cells, respectively. We concluded that encapsulated hepatocyte spheroids in a packed-bed bioreactor operated with human plasma including trace elements enhanced cell viability and liver function as a bases for an in vivo clinical trial of the BAL system.

Fulminant hepatic failure and serum phosphorus levels in children from the western part of Turkey.

BACKGROUND/AIMS: Clinical and laboratory predictors of recovery in children with fulminant hepatic failure are limited. Recently, hypophosphatemia has been reported as a laboratory indicator of recovering liver function in children with fulminant hepatic failure . We aimed to determine the incidence of hypophosphatemia and its association with clinical outcome in children in our center with fulminant hepatic failure. METHODS: We analyzed 21 children who had been diagnosed with fulminant hepatic failure. Laboratory findings were recorded from admission date until the patient spontaneously recovered, underwent orthotopic liver transplantation or died. RESULTS: Eight patients (38%) died, 6 (28.6%) underwent orthotopic liver transplantation, and 7 (33.3%) recovered without orthotopic liver transplantation. We identified hypophosphatemia in 57.1% of children with fulminant hepatic failure. Serum phosphorus levels were significantly lower in patients who recovered than in the orthotopic liver transplantation+death group. The presence of encephalopathy was determined at a much lower rate in the recovery group than in the orthotopic liver transplantation+death group. Serum phosphorus concentration ≥2.9 mg/dl and presence of encephalopathy were identified as independent risk factors for mortality. CONCLUSIONS: Hypophosphatemia can be identified as a marker of recovery in children with fulminant hepatic failure. Presence of encephalopathy and a serum phosphorus level ≥2.9 mg/dl appear to indicate a poor prognosis in children with fulminant hepatic failure.

Transient acute liver failure complicating transurethral resection syndrome.

Transurethral resection (TUR) syndrome, resulting from dilutional hyponatraemia for excessive absorption of irrigating fluid, represents the most relevant complication of transurethral resection of prostate (TURP). Ethanol is used as a tracer in the irrigant solution to monitor fluid absorption with a breathalyser. An unusual case of transient acute liver failure complicating TUR syndrome is reported. A 54-year-old male patient, without risk factors for the development of toxic hepatitis, was subjected to TURP for treatment of benign prostatic hyperplasia. Fluid absorption (2275 ml), estimated by breathalyser, exceeded maximum allowed absorption (2000 ml) only at the end of the surgical intervention. No signs of possible toxicity were evident in the few hours following the intervention. About 10 h after the end of TURP, the patient developed sweating, vomiting and diarrhoea. Laboratory analysis revealed severe hyponatraemia (116 meq/l) with signs of severe liver impairment (total bilirubin 5.8 mg/dl, alanine aminotransferase 56,500 U/l, aspartate aminotransferase 32,700 U/l), kidney failure (serum creatinine 1.93 mg/dl) and serum ethanol levels of 219 mg/dl (0.2%). The patient was treated with acetylcysteine 150 mg/kg i.v. and furosemide 50 mg i.v. Liver and renal functions improved in few days and recovered completely within 30 days. The TUR syndrome observed in this case was probably extravascular in nature, and could have been identified and prevented by measuring ethanol levels 10 min after ending the surgical procedure. The performance of such a test should be strongly recommended to all surgeons. The clinicians attributed the development of liver impairment in this case to ethanol toxicity. However, further studies are warranted to confirm whether hepatic injury can represent a possible complication of TUR syndrome when ethanol solution is used as irrigant fluid.

Protective effect of a mixture of Aloe vera and Silybum marianum against carbon tetrachloride-induced acute hepatotoxicity and liver fibrosis.

The hepatoprotective effects of ACTIValoe N-931 complex, a mixture of Aloe vera and Silybum marianum, against acute and chronic carbon tetrachloride (CCl(4))-induced liver injuries were investigated. Acute hepatotoxicity was induced by intraperitoneal injection of CCl(4) (50 microl/kg), and ACTIValoe N-931 complex at 85, 170, and 340 mg/kg was administered orally 48, 24, and 2 h before and 6 h after injection of CCl(4). Hepatotoxicity was assessed 24 h after CCl(4) treatment. Liver fibrosis was induced by intraperitoneal injection of CCl(4) for 8 weeks (0.5 ml/kg, twice per week), and mice were treated with ACTIValoe N-931 complex at 85, 170, or 340 mg/kg once a day (p.o.). In both acute hepatotoxicity and liver fibrosis, serum aminotransferase levels and lipid peroxidation were increased and the hepatic glutathione content was decreased. These changes were prevented by ACTIValoe N-931 complex. The ACTIValoe N-931 complex attenuated the increase in tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), mRNA expressions in acute hepatotoxicity. In antifibrotic experiments, tissue inhibitor of metalloprotease-1 (TIMP-1) mRNA expression was attenuated by treatment with ACTIValoe N-931 complex. The ACTIValoe N-931 complex decreased the hepatic hydroxyproline content and the transforming growth factor-beta1 levels. Our results suggest that the ACTIValoe N-931 complex has hepatoprotective effects in both acute and chronic liver injuries induced by CCl(4).

[Therapeutic effect of the latest extracorporal elimination procedure (Prometheus treatment) in acute liver failure caused by intoxication]. / A legújabb extracorporalis eliminációs eljárás (Prometheus-kezelés) terápiás hatékonysága mérgezés okozta akut májelégtelenségben.

INTRODUCTION: Despite intensive therapy the mortality of acute liver failure without organ transplantation is 60-90%. Because of organ shortage in liver transplantation, a significant number of patients dies while being on the waiting list. In order to diminish the mortality, various trials were introduced to remove the albumin-bound and water-soluble toxins in liver failure with the aim to support the spontaneous regeneration of the liver and maintaining the patients alive until liver transplantation. Prometheus treatment is a relatively new technique combining Fractionated Plasma Separation and Adsorption (FPSA) with a high-flux dialysis. During the procedure the patient's own separated albumin-rich plasma passes through special adsorbents making possible the elimination of albumin-bound toxins, while hemodialysis gets rid of water-soluble toxins. AIM: The authors' intention was to demonstrate the efficiency of Prometheus treatment in acute liver failure caused by intoxication. PATIENTS AND METHOD: Prometheus treatment was indicated in three patients who suffered from severe intoxication with paracetamol, potassium permanganate and Amanita phalloides, which resulted in a hepatic failure incurable with conservative therapy. RESULTS: Ten treatments were performed in the three female patients. No serious complication was observed. Due to the treatment the albumin-bound (indirect bilirubin p = 0.048; bile acid p = 0.001) and water-soluble (direct bilirubin p = 0.002; creatinine p = 0.007) toxins were significantly decreased. The level of ammonia, urea nitrogen, fibrinogen and antithrombin III did not change significantly. All the three patients were cured without liver transplantation. CONCLUSION: Prometheus treatment removes efficiently the accumulating toxins in acute liver failure. It is a safe elimination technique. In cases untreatable with conservative therapy it makes possible maintaining the patients alive until the liver regenerates spontaneously, or liver transplantation is feasible.

[Effect of Suanzaoren decoction on acute hepatic failure in mice].

OBJECTIVE: To investigate the effect of Suanzao nacute hepatic failure in mice. METHOD: Acute liver failure was induced in male Kunming strain mice by enterocoelia injecting the animals with D-Gal-N and LPS. The mice in treatment groups were given corresponding drug 2 h before administration of D-Ga1-N and LPS, and the mice in control group were given the same dose of distilled water. The 24 h survival rate, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels were compared. Serum the levels of TNF-alpha and IL-1 and the levels of SOD, MDA, GR, GSH, NO and NOS in the liver were determined. RESULT: Treatment with suanzaoren decoction could increase the survival rate and improve the liver histological feather. Suanzaoren decoction inhibited the serum the levels of ALT, AST, TNF-alpha and IL-1, and reduced the levels of MDA, NO and NOS and increased the levels of GR and SOD in the liver. CONCLUSION: Treatment with Suanzaoren decoction can suppress the D-Gal-N/LPS-induced acute hepatic failure. It may be the mechanism that Suanzaoren decocotion regulate the production of inflammatory cytokines and free radicals.

[The use of cryopreserved hepatocytes in the combined treatment of patients with acute liver failure]. / Primenenie kriokonservirovannykh gepatotsitov v kompleksnom lechenii bol'nykh s ostroi pechenochnoi nedostatochnost'iu.

Shown in the paper is employment of one of the modern modalities of treatment of acute hepatic insufficiency (AHI)--that of "cell dialysis" involving the use of freeze-preserved hepatocytes. Hepatic insufficiency develops as a result of poisoning with hepatotrophic poisons (chlorinated hydrocarbons, poisonous mushrooms). The principle of commonly practised hemodialysis is the basis of "cell dialysis" but it was hepatocytes mixture in Hank's solution that was used as a dialysis solution. The time-related course was studied of clinical, laboratory findings. The inclusion of "cell dialysis" into the complex of active methods of detoxication was found to bring about an appreciable decline in mortality among AHI patients together with a reduction of their hospital stay.

Two models of acute hepatic failure with extensive hepatic necrosis and blood ammonia elevation in small animals.

Acute hepatic failure models with extensive hepatic necrosis and hyperammonemia were developed in small animals. One model is bases on the retrograde infusion of ethanolamine oleate into the common bile duct of guinea pigs and another is based on the infusion of TNF-lipiodol emulsion into the portal tract of rats.