The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma.

INTRODUCTION: Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED: We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION: microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.

Upregulation of miR-142-5p induced by lipopolysaccharide contributes to apoptosis of hepatocytes and hepatic failure.

OBJECTIVE: This study was probed to uncover the mechanism of miR-142-5p in septic liver injury. MATERIALS AND METHODS: In this study, in-vitro and in-vivo models of sepsis were used. For in-vitro sepsis model, hepatocyte cell line (L02 cells) was treated with LPS (lipopolysaccharide). Whereas for in-vivo sepsis model, cecal ligation and puncture were performed in mice. Mice were assigned into three groups: control, CLP (Cecal Ligation Puncture), CLP + miR-142-5p inhibitor group. Liver injury was assessed via H&E staining. IL-6, TNF-α, and IL-1ß expressions were assayed through ELISA kits. C-caspase-9, C-caspase-3, ERK, p65, and IκBα expressions were determined via western blot and RT-qPCR. Apoptosis in LPS-induced L02 cells was detected by TUNEL staining. RESULTS: Our results show that miR-142-5p exhibited perspicuous upregulation in CLP mice tissues and LPS-induced L02 cells. On the other hand, inhibition of miR-142-5p could promote LPS-induced L02 cell activity and reduce apoptosis and inflammation. In terms of molecular mechanism, downregulation of miR-142-5p could abate sepsis-mediated acute hepatic injury by targeting SOCS1, through ERK and NF-κB pathway. CONCLUSIONS: Overall our results demonstrate that miR-142-5p inhibitors can mitigate septic liver injury by downregulating the inflammation and apoptosis via targeting SOCS1. Thus, miR-142-5p can serve a potential therapeutic target for sepsis mediated acute hepatic injury.

Utility of remnant liver volume for predicting posthepatectomy liver failure after hepatectomy with extrahepatic bile duct resection.

BACKGROUND: Hepatectomy with extrahepatic bile duct resection is associated with a high risk of posthepatectomy liver failure (PHLF). However, the utility of the remnant liver volume (RLV) in cholangiocarcinoma has not been studied intensively. METHODS: Patients who underwent major hepatectomy with extrahepatic bile duct resection between 2002 and 2018 were reviewed. The RLV was divided by body surface area (BSA) to normalize individual physical differences. Risk factors for clinically relevant PHLF were evaluated with special reference to the RLV/BSA. RESULTS: A total of 289 patients were included. The optimal cut-off value for RLV/BSA was determined to be 300 ml/m2. Thirty-two patients (11.1 per cent) developed PHLF. PHLF was more frequent in patients with an RLV/BSA below 300 ml/m2 than in those with a value of 300 ml/m2 or greater: 19 of 87 (22 per cent) versus 13 of 202 (6.4 per cent) (P < 0.001). In multivariable analysis, RLV/BSA below 300 ml/m2 (P = 0.013), future liver remnant plasma clearance rate of indocyanine green less than 0.075 (P = 0.031), and serum albumin level below 3.5 g/dl (P = 0.015) were identified as independent risk factors for PHLF. Based on these risk factors, patients were classified into three subgroups with low (no factors), moderate (1-2 factors), and high (3 factors) risk of PHLF, with PHLF rates of 1.8, 14.8 and 63 per cent respectively (P < 0.001). CONCLUSION: An RLV/BSA of 300 ml/m2 is a simple predictor of PHLF in patients undergoing hepatectomy with extrahepatic bile duct resection.

Haemophagocytic lymphohistiocytosis and liver failure-induced massive hyperferritinaemia in a male COVID-19 patient.

The authors present the case of a 58-year-old man with the unique combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and, later on, haemophagocytic lymphohistiocytosis admitted to the intensive care unit. During his ICU stay the patient developed a variety of complications including acute respiratory distress syndrome, pulmonary embolism, right heart failure and suspected HLH leading to multiorgan failure and death. Despite the proven diagnosis of haemophagocytic lymphohistiocytosis, the excessively high ferritin levels of the patient did not seem fully explained by this diagnosis. Therefore, the authors want to highlight different causes of hyperferritinaemia in critically ill patients and underline the importance of differential diagnoses when interpreting continuously rising ferritin levels.

Fulminant Bacillus cereus food poisoning with fatal multi-organ failure.

This case represents a rare fulminant course of fried-rice associated food poisoning in an immunocompetent person due to pre-formed exotoxin produced by Bacillus cereus, with severe manifestations of sepsis, including multi-organ (hepatic, renal, cardiac, respiratory and neurological) failure, shock, metabolic acidosis, rhabdomyolysis and coagulopathy. Despite maximal supportive measures (continuous renal replacement therapy, plasmapheresis, N-acetylcysteine infusion and blood products, and broad-spectrum antimicrobials) and input from a multidisciplinary team (consisting of infectious diseases, intensive care, gastroenterology, surgery, toxicology, immunology and haematology), mortality resulted. This case is the first to use whole genome sequencing techniques to confirm the toxigenic potential of B. cereus It has important implications for food preparation and storage, particularly given its occurrence in home isolation during the COVID-19 pandemic.

Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure.

Hepatectomy is an effective therapeutic strategy for many benign and malignant liver diseases, while the complexity of liver anatomy and the difficulty of operation lead to complications after hepatectomy. Among them, post-hepatectomy liver failure (PHLF) is the main factor threatening the life of patients. At present, liver transplantation is an effective approach for PHLF. However, the application of liver transplantation has been largely limited due to the shortage of donors and the high cost of such operation. Therefore, it is urgently necessary to develop a new treatment for PHLF. Mesenchymal stem cells (MSCs) have become a new treatment regimen for liver diseases because of their easy access and low immunogenicity. Our study found that there were some subtle connections between MSCs and liver lipid metabolism in the PHLF model. We used MSC transplantation to treat PHLF induced by 90% hepatectomy. MSC transplantation could restore the mitochondrial function, promote the ß-oxidation of fatty acid (FA), and reduce the lipid accumulation of hepatocytes. In addition, interleukin 10 (IL-10), a cytokine with immunoregulatory function, had an important role in lipid metabolism. We also found that MSCs transplantation activated the mammalian target of rapamycin (mTOR) pathway. Therefore, we explored the relationship between mitochondrial damage and lipid metabolism abnormality or PHLF. MSCs improved mitochondrial function and corrected abnormal lipid metabolism by affecting the mTOR pathway in the treatment of PHLF. Collectively, MSC transplantation could be used as a potential treatment for PHLF.

Dose adjustment for tyrosine kinase inhibitors in non­small cell lung cancer patients with hepatic or renal function impairment (Review).

In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non­small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.

Intraoperative Increase of Portal Venous Pressure is an Immediate Predictor of Posthepatectomy Liver Failure After Major Hepatectomy: A Prospective Study.

OBJECTIVES: The aim of this study was to assess intraoperative changes of hepatic macrohemodynamics and their association with ascites and posthepatectomy liver failure (PHLF) after major hepatectomy. SUMMARY OF BACKGROUND DATA: Large-scale ascites and PHLF remain clinical challenges after major hepatectomy. No study has concomitantly evaluated arterial and venous liver macrohemodynamics in patients undergoing liver resection. METHODS: Portal venous pressure (PVP), portal venous flow (PVF), and hepatic arterial flow (HAF) were measured intraoperatively pre- and postresection in 67 consecutive patients with major hepatectomy (ie, resection of ≥3 liver segments). A group of 30 patients with minor hepatectomy served as controls. Liver macrohemodynamics and their intraoperative changes (ie, Δ) were analyzed as predictive biomarkers of ascites and PHLF using Fisher exact, t test, or Wilcoxon rank sum test for univariate and logistic regression for multivariate analyses. RESULTS: Major hepatectomy increased PVP by 26.9% (P = 0.001), markedly decreased HAF by 40.7% (P < 0.001), and slightly decreased PVF by 13.4% (P = 0.011). Minor resections had little effects on hepatic macrohemodynamics. There was no significant association of liver macrohemodynamics with ascites. While middle hepatic vein resection caused higher postresection PVP after right hepatectomy (P = 0.04), the Pringle maneuver was associated with a significant PVF (P = 0.03) and HAF reduction (P = 0.03). Uni- and multivariate analysis revealed an intraoperative PVP increase as an independent predictor of PHLF (P = 0.025). CONCLUSION: Intraoperative PVP kinetics serve as independent predictive biomarker of PHLF after major hepatectomy. These data highlight the importance to assess intraoperative dynamics rather than the pre- and postresection PVP values.

Issues to be considered to address the future liver remnant prior to major hepatectomy.

An accurate preoperative evaluation of the hepatic function and application of portal vein embolization in selected patients have helped improve the safety of major hepatectomy. In planning major hepatectomy, however, several issues remain to be addressed. The first is which cut-off values for serum total bilirubin level and prothrombin time should be used to define post-hepatectomy liver failure. Other issues include what minimum future liver remnant (FLR) volume is required; whether the total liver volume measured using computed tomography or the standard liver volume calculated based on the body surface area should be used to assess the adequacy of the FLR volume; whether there is a discrepancy between the FLR volume and function during the recovery period after portal vein embolization or hepatectomy; and how best the function of a specific FLR can be assessed. Various studies concerning these issues have been reported with controversial results. We should also be aware that different strategies and management are required for different types of liver damage, such as cirrhosis in hepatocellular carcinoma, cholangitis in biliary tract cancer, and chemotherapy-induced hepatic injury.

Evolución de los pacientes con enfermedad hepática crítica / Prognosis of patients with critical hepatic disease

INTRODUCTION: The acute liver failure on chronic (ACLF), is an entity, whose recognition is increasing. The ACLF and CLIF OF indexes have been recently presented with the objective of predicting mortality in this kind of patients. MATERIAL AND METHODS: All patients admitted to the Ramón y Cajal University Hospital diagnosed of acute liver failure on chronic during 2016 and 2017 were collected. We collect the scores: SOFA, CLIF, APACHE II, SAPS II and ACLF score in patients admitted to the ICU by comparing them with each other and define which stages have worse prognosis. RESULTS: A total of 46 patients were collected. The study presents an intra ICU mortality of 31% (15/46) and a six-month mortality of 59.6% (28/46). Patients classified as death, present ACLF values ​​at admission (49.5 vs 60 p = 0.001), and at three days (46.66 vs 59.4 p = 0.001) higher than survivors. In the analysis of the ROC curve, the area under the curve in relation to six-month mortality is higher in the ACLF index (0.8) compared to the MELD (0.69) SOFA (0.66) SAPS II (0.69) or APACHE II (0.65). Patients with ACLF indexes above 65 had an intra UCI mortality of 54%, however, mortality at 6 months is 90%. Patients with ACLF values ​​greater than 65 present mean values ​​of lactic acid, leukocytes, INR or bilirubin higher than those under 65 in a statistically significant manner. CONCLUSIONS: The data presented in this study suggest that the ACLF index works as an adequate predictor of intra-ICU mortality and at 6 months.

INTRODUCCIÓN: El fallo hepático agudo sobre crónico es una entidad cuyo reconocimiento va en aumento. Los índices ACLF y CLIF OF, han sido presentados recientemente con el objetivo de predecir la mortalidad en este tipo de enfermos. MATERIAL Y MÉTODOS: Se recogen todos los pacientes ingresados en una unidad de cuidados intensivos (UCI) de un hospital terciario universitario, diagnosticados de fallo hepático agudo sobre crónico durante 2016 y 2017. Recogemos los índices SOFA, CLIF, APACHE II, SAPS II Y ACLF en pacientes ingresados en UCI comparándolos entre sí. Definimos que estadios presentan peor pronóstico. RESULTADOS: Se analizan un total de 46 pacientes. El estudio presenta una mortalidad intra-UCI del 31% (15/46) y una mortalidad a los seis meses de 59,6% (28/46). Los pacientes clasificados como éxitus presentan valores ACLF al ingreso (49,5 vs 60 p = 0,001), a los tres días (46,66 vs 59,4 p = 0,001) superiores a los supervivientes. En el análisis de la curva COR, el área bajo la curva en relación a la mortalidad a los seis meses, es superior en el índice ACLF (0,8) en comparación con el MELD (0,69) SOFA (0,66) SAPS II (0,69) o APACHE II (0,65). Los pacientes con índices ACLF superiores a 65 presentaban una mortalidad intra-UCI del 54% sin embargo, la mortalidad a los 6 meses es del 90%. Los pacientes con valores ACLF superiores a 65 presentan a su vez valores medios de láctico, leucocitos, INR o bilirrubina mayores de forma estadísticamente significativa. CONCLUSIONES: Los datos presentados en este estudio sugieren que el índice ACLF funciona como un adecuado predictor de mortalidad intra-UCI y a los 6 meses.

Identification of exacerbation risk in patients with liver dysfunction using machine learning algorithms.

The prediction of the liver failure (LF) and its proper diagnosis would lead to a reduction in the complications of the disease and prevents the progress of the disease. To improve the treatment of LF patients and reduce the cost of treatment, we build a machine learning model to forecast whether a patient would deteriorate after admission to the hospital. First, a total of 348 LF patients were included from May 2011 to March 2018 retrospectively in this study. Then, 15 key clinical indicators are selected as the input of the machine learning algorithm. Finally, machine learning and the Model for End-Stage Liver Disease (MELD) are used to forecast the LF deterioration. The area under the receiver operating characteristic (AUC) of MELD, GLMs, CART, SVM and NNET with 10 fold-cross validation was 0.670, 0.554, 0.794, 0.853 and 0.912 respectively. Additionally, the accuracy of MELD, GLMs, CART, SVM and NNET was 0.669, 0.456, 0.794, 0.853 and 0.912. The predictive performance of the developed machine model execept the GLMs exceeds the classic MELD model. The machine learning method could support the physicians to trigger the initiation of timely treatment for the LD patients.

Impact of COVID-19 on liver function: results from an internal medicine unit in Northern Italy.

Little is known regarding coronavirus disease 2019 (COVID-19) clinical spectrum in non-Asian populations. We herein describe the impact of COVID-19 on liver function in 100 COVID-19 consecutive patients (median age 70 years, range 25-97; 79 males) who were admitted to our internal medicine unit in March 2020. We retrospectively assessed liver function tests, taking into account demographic characteristics and clinical outcome. A patient was considered as having liver injury when alanine aminotransferase (ALT) was > 50 mU/ml, gamma-glutamyl transpeptidase (GGT) > 50 mU/ml, or total bilirubin > 1.1 mg/dl. Spearman correlation coefficient for laboratory data and bivariable analysis for mortality and/or need for intensive care were assessed. A minority of patients (18.6%) were obese, and most patients were non- or moderate-drinkers (88.5%). Liver function tests were altered in 62.4% of patients, and improved during follow-up. None of the seven patients with known chronic liver disease had liver decompensation. Only one patient developed acute liver failure. In patients with altered liver function tests, PaO2/FiO2 < 200 was associated with greater mortality and need for intensive care (HR 2.34, 95% CI 1.07-5.11, p = 0.033). To conclude, a high prevalence of altered liver function tests was noticed in Italian patients with COVID-19, and this was associated with worse outcomes when developing severe acute respiratory distress syndrome.

Liver stiffness measured by acoustic radiation force impulse elastography predicted prognoses of hepatocellular carcinoma after radiofrequency ablation.

The prognostic factors of patients who undergo radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is not fully elucidated. We aimed to investigate the role of liver stiffness (LS) and spleen stiffness (SS) measured by acoustic radiation force impulse (ARFI) elastography in determining the prognoses of patients with HCC after RFA. We prospectively enrolled 173 patients with HCC who underwent ARFI elastography for measurement of LS and SS on the same day of RFA. Overall survival (OS), recurrence-free survival (RFS) after adjusting for competing mortality, and presence of hepatic decompensation were investigated. Patients with LS > 1.5 m/s had significantly shorter OS and RFS than their counterparts. Anti-viral treatment (hazard ratio [HR]: 0.396, p = 0.015) and LS > 1.5 m/s (HR 4.105, p = 0.028) correlated with OS by a multivariate analysis. Besides, serum alpha fetoprotein >10 ng/mL and LS > 1.5 m/s independently predicted poorer RFS. On the other hand, anti-viral treatment (HR: 0.315, p = 0.010), creatinine > 1.5 mg/dL (HR: 9.447, p = 0.006), and SS > 2.7 m/s (HR: 2.869, p = 0.044) predicted a higher risk of hepatic decompensation. In conclusion, LS but not SS measured by ARFI elastography predicted tumor recurrence and OS in RFA-treated HCC; whereas, SS predicted development of hepatic decompensation in these patients.

Extracorporeal liver support in patients with liver failure: a systematic review and meta-analysis of randomized trials.

PURPOSE: Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure. METHODS: We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence. RESULTS: We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain. CONCLUSIONS: ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.

Autoimmune Hepatic Failure Following Acute Hepatitis A is Accompanied by Inflammatory Conversion of Regulatory T Cells.

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, we performed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantation due to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remained high for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells into mediators of inflammation may have played a role in the autoimmune pathogenesis following AHA.

Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview.

Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case.

Placenta derived factors involved in the pathogenesis of the liver in the syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP): A review.

AIM: With this review we try to unravel if placenta-derived factors are able to initiate liver sinusoidal endothelial cells (LSEC) decay in HELLP syndrome and eventually cause the development of sinusoidal obstruction syndrome (SOS). BACKGROUND: Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome is a severe complication of pregnancy. It is characterized by elevated liver enzymes, low platelet count and haemolytic anaemia. The risk of developing HELLP syndrome within a pregnancy is 0.1-0.8%. The mortality rate among women with HELLP syndrome is 0-24% and the perinatal death goes up to 37%. The aetiology of HELLP syndrome is not fully understood but the pathogenesis of the liver pathology in the HELLP syndrome resembles that of a SOS with endothelial damage of the LSECs which ultimately leads to liver failure. OBJECTIVES: We hypothesize that placenta derived factors cause LSEC damage and thereby liver dysfunction. METHODS: We searched in the PubMed database for relevant articles about placenta derived factors involved in endothelial activation especially in the liver. We yielded eventually 55 relevant articles. RESULTS: Based on this literature search we associate that in HELLP syndrome there is an increase of soluble fms-like tyrosine kinase (sFlt1), vascular endothelial growth factor (VEGFR), soluble endoglin (sEng), galectin-1 (Gal-1), endothelin-1 (ET-1), Angiopoietin 2 (Angs-2), Asymmetric dimethylarginine (ADMA), activin B, inhibin A, Fas ligand (FasL) and heat shock protein 70 (Hsp70). CONCLUSION: We assume that these eleven increased placenta derived factors are responsible for LSEC damage which eventually leads to liver failure. This concept shows a possible design of the complicated pathophysiology in HELLP syndrome. However further research is required.

Evaluation of liver regeneration and post-hepatectomy liver failure after hemihepatectomy in patients with hepatocellular carcinoma.

Aim: To explore clinical factors associated with extent of liver regeneration after hemihepatectomy to treat hepatocellular carcinoma (HCC).Methods: Future liver remnant volume (as a percentage of functional liver volume, %FLRV) and remnant liver volume were measured preoperatively and at 1, 5, 9, and 13 weeks postoperatively.Results: After hepatectomy, 1 of 125 patients (0.8%) died within 3 months, 13 (10.4%) experienced liver failure, and 99 (79.2%) experienced complications. %FLRV was able to predict liver failure with an area under the receiver operating characteristic curve of 0.900, and a cut-off value of 42.7% showed sensitivity of 85.7% and specificity of 88.6%. Postoperative median growth ratio was 21.3% at 1 week, 30.9% at 5 weeks, 34.6% at 9 weeks, and 37.1% at 13 weeks. Multivariate analysis identified three predictors associated with liver regeneration: FLRV < 601 cm3, %FLRV, and liver cirrhosis. At postoperative weeks (POWs) 1 and 5, liver function indicators were significantly better among patients showing high extent of regeneration than among those showing low extent, but these differences disappeared by POW 9.Conclusions: FLRV, %FLRV, and liver cirrhosis strongly influence extent of liver regeneration after hepatectomy. %FLRV values below 42.7% are associated with greater risk of post-hepatectomy liver failure.

Porcine model for the study of liver regeneration enhanced by non-invasive 13C-methacetin breath test (LiMAx test) and permanent portal venous access.

INTRODUCTION: Despite advances in perioperative management and surgical technique, postoperative liver failure remains a feared complication after hepatic resection. Various supportive treatment options are under current discussion, but lack of structured evaluation. We therefore established a porcine model of major liver resection to study regeneration after partial hepatectomy in a reliable and well-defined pre-clinical setting. METHODS: Major hepatectomy was performed on seven minipigs with the intention to set up a non-lethal but relevant transient impairment of liver function. For steady postoperative vascular access (e.g. for blood withdrawal, measurement of venous pressure), permanent catheters were implanted into the internal jugular and portal veins, respectively. Animals were followed up for 30 days; clinical and laboratory results were recorded in detail. Monitoring was enhanced by non-invasive determination of the maximum liver function capacity (LiMAx test). RESULTS AND CONCLUSIONS: The established porcine model appeared suitable for evaluation of postoperative liver regeneration. Clinical characteristics and progression of liver function impairment as well as subsequent recovery were comparable to courses known from surgery in humans. Laboratory parameters (e.g. liver enzymes, bilirubin, INR, coagulation factor II) showed relevant derangements during postoperative days (POD) 0 to 3 followed by normalization until POD 7. Application of the LiMAx test was feasible in minipigs, again showing values comparable to humans and kinetics in line with obtained laboratory parameters. The exteriorized portal vein catheters enabled intra- and postoperative monitoring of portal venous pressures as well as easy access for blood withdrawal without relevant risk of postoperative complications.

Prognostic value of hepatic encephalopathy for survival of patients with liver failure: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: The aim of this paper was to evaluate the association of hepatic encephalopathy with survival of patients with liver failure. MATERIALS AND METHODS: We retrieved the relevant articles from the PubMed, Embase and Cochrane Library, up to May 2017. The pooled odds ratio (OR) as well as their 95% confidence intervals (CI) was calculated by the software of R package version 3.12. RESULTS: Total 13 studies with 2071 liver failure patients were included and reanalyzed in this meta-analysis. The results proved the prognostic value of hepatic encephalopathy for survival of patients with liver failure (OR=5.62, 95%CI=6.30-9.82, P<0.001). The subgroup analyses showed that the type of liver failure and the follow up duration may be the factor influencing the association between hepatic encephalopathy and survival of patients with liver failure. CONCLUSIONS: The results proved that hepatic encephalopathy was a prognostic factor of survival in patients with liver failure.