Dataset Information

Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

ABSTRACT: Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, and at 48 hours following hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24-48 hours after hepatectomy: Group1-standard medical therapy (SMT, n = 6); Group2-SMT plus bio-artificial liver treatment using no hepatocytes (0 g, n = 6); and Group3-SMT plus SRBAL treatment using 200 g of primary porcine hepatocyte spheroids (200 g, n = 6). The primary endpoint was survival to 90 hours following hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP greater than 20 mmHg with clinical evidence of brain herniation. All animals in both (SMT and 0 g) control groups met the death equivalent before 51 hours following hepatectomy. Five of 6 animals in the 200-g group survived to 90 hours (P < 0.01). The mean ammonia, ICP, and international normalized ratio values were significantly lower in the 200-g group. CT volumetrics demonstrated increased volume regeneration at 48 hours following hepatectomy in the 200-g group compared with the SMT (P < 0.01) and 0-g (P < 0.01) groups. Ki-67 staining showed increased positive staining at 48 hours following hepatectomy (P < 0.01). Conclusion: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in posthepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL.

SUBMITTER: Chen HS

PROVIDER: S-EPMC6527364 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

Chen Harvey S HS Joo Dong Jin DJ Shaheen Mohammed M Li Yi Y Wang Yujia Y Yang Jian J Nicolas Clara T CT Predmore Kelly K Amiot Bruce B Michalak Gregory G Mounajjed Taofic T Fidler Jeff J Kremers Walter K WK Nyberg Scott L SL

Hepatology (Baltimore, Md.) 20181227 1

Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, a ...[more]

PMID: 30022502

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Project description:ObjectivesPosthepatectomy liver failure (PHLF) is a severe complication of liver resection. We aimed to develop and validate a model based on extracellular volume (ECV) and liver volumetry derived from computed tomography (CT) for preoperative predicting PHLF in resectable hepatocellular carcinoma (HCC) patients.MethodsA total of 393 resectable HCC patients from two hospitals were enrolled and underwent multiphasic contrast-enhanced CT before surgery. A total of 281 patients from our hospital were randomly divided into a training cohort (n = 181) and an internal validation cohort (n = 100), and 112 patients from another hospital formed the external validation cohort. CT-derived ECV was measured on nonenhanced and equilibrium phase images, and liver volumetry was measured on portal phase images. The model is composed of independent predictors of PHLF. The under the receiver operator characteristic curve (AUC) and calibration curve were used to reflect the predictive performance and calibration of the model. Comparison of AUCs used the DeLong test.ResultsCT-derived ECV, measured future liver remnant (mFLR) ratio, and serum albumin were independent predictors for PHLF in resectable HCC patients. The AUC of the model was significantly higher than that of the ALBI score in the training cohort, internal validation cohort, and external validation cohort (all p < 0.001). The calibration curve of the model showed good consistency in the training cohort and the internal and external validation cohorts.ConclusionsThe novel model contributes to the preoperative prediction of PHLF in resectable HCC patients.Critical relevance statementThe novel model combined CT-derived extracellular volume, measured future liver remnant ratio, and serum albumin outperforms the albumin-bilirubin score for predicting posthepatectomy liver failure in patients with resectable hepatocellular carcinoma.Key points• CT-derived ECV correlated well with the fibrosis stage of the background liver. • CT-derived ECV and mFLR ratio were independent predictors for PHLF in HCC. • The AUC of the model was higher than the CT-derived ECV and mFLR ratio. • The model showed a superior predictive performance than that of the ALBI score.

Project description:BackgroundPosthepatectomy liver failure (PHLF) represents a life-threatening complication with limited therapeutic options. Neutrophils play a critical and dynamic role during regeneratory processes, but their role in human liver regeneration is incompletely understood, especially as underlying liver disease, detectable in the majority of patients, critically affects hepatic regeneration. Here we explored intrahepatic neutrophil accumulation and neutrophil extracellular traps (NETs) in patients with PHLF and validated the functional relevance of NETs in a murine partial hepatectomy (PHx) model.MethodsWe investigated the influx of neutrophils, macrophages, eosinophils, and mast cells and the presence of their respective extracellular traps in liver biopsies of 35 patients undergoing hepatectomy (10 patients with PHLF) before and after the initiation of liver regeneration by fluorescence microscopy. In addition, NET formation and neutrophil activation were confirmed by plasma analysis of 99 patients (24 patients with PHLF) before and up to 5 days after surgery. Furthermore, we inhibited NETs via DNase I in a murine PHx model of mice with metabolically induced liver disease.ResultsWe detected rapid intrahepatic neutrophil accumulation, elevated levels of myeloperoxidase release, and NET formation in regenerating human livers, with a significantly higher increase of infiltrating neutrophils and NETs in patients with PHLF. Circulating markers of neutrophil activation, including elastase, myeloperoxidase, and citrullinated histone H3, correlated with markers of liver injury. In a murine PHx model, we showed that the inhibition of NET accelerated hepatocyte proliferation and liver regeneration.ConclusionsPatients with PHLF showed accelerated intrahepatic neutrophil infiltration and NET formation, which were associated with liver damage. Further, we identified postsurgical myeloperoxidase levels as predictive markers for adverse outcomes and observed that blocking NETs in a murine PHx model accelerated tissue regeneration.

Project description:Rationale: Acute liver failure (ALF) causes severe liver injury and a systemic inflammatory response, leading to multiorgan failure with a high short-term mortality. Bioartificial liver (BAL) therapy is a promising approach that is hampered by the lack of appropriate bioreactors and carriers to retain hepatic cell function and poor understanding of BAL treatment mechanisms in ALF and extrahepatic organ injury. Recently, we used a fiber scaffold bioreactor (FSB) for the high-density, three-dimensional (3D) culture of primary porcine hepatocytes (PPHs) combined with an absorption component to construct a BAL and verified its function in a D-galactosamine (D-gal)-induced ALF porcine model to evaluate its protective effects on the liver and extrahepatic organs. Methods: Male pigs were randomized into standard/supportive therapy (ST), ST+no-cell BAL (ST+Sham BAL) and ST+BAL groups and received treatment 48 h after receiving a D-gal injection. Changes in blood chemistry and clinical symptoms were monitored for 120 h. Tissues and plasma were collected for analysis by pathological examination, immunoblotting, quantitative PCR and immunoassays. Results: PPHs cultured in the FSB obtained sufficient aeration and nutrition for high-density, 3D culture and maintained superior viability and functionality (biosynthesis and detoxification) compared with those cultured in flasks. All the animals developed ALF, acute kidney injury (AKI) and hepatic encephalopathy (HE) 48 h after D-gal infusion and received corresponding therapies. Animals in the BAL group showed markedly improved survival (4/5; 80%) compared with those in the ST+Sham BAL (0/5; p < 0.001) and ST (0/5; p < 0.001) groups. The levels of blood ammonia and biochemical and inflammatory indices were alleviated after BAL treatment. Increased liver regeneration and attenuations in the occurrence and severity of ALF, AKI and HE were observed in the ST+BAL group compared with the ST (p = 0.0009; p = 0.038) and ST+Sham BAL (p = 0.011; p = 0.031) groups. Gut leakage, the plasma endotoxin level, bacterial translocation, and peripheral and neuroinflammation were alleviated in the ST+BAL group compared with those in the other groups. Conclusions: BAL treatment enhanced liver regeneration and alleviated the systemic inflammatory response and extrahepatic organ injury to prolong survival in the ALF model and has potential as a therapeutic approach for ALF patients.

Dataset Information

Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

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Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

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