Characteristics of circulating immune cells in HBV-related acute-on-chronic liver failure following artificial liver treatment.

BACKGROUND AND AIM: Liver failure, which is predominantly caused by hepatitis B (HBV) can be improved by an artificial liver support system (ALSS). This study investigated the phenotypic heterogeneity of immunocytes in patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) before and after ALSS therapy. METHODS: A total of 22 patients with HBV-ACLF who received ALSS therapy were included in the study. Patients with Grade I according to the ACLF Research Consortium score were considered to have improved. Demographic and laboratory data were collected and analyzed during hospitalization. Immunological features of peripheral blood in the patients before and after ALSS were detected by mass cytometry analyses. RESULTS: In total, 12 patients improved and 10 patients did not. According to the immunological features data after ALSS, the proportion of circulating monocytes was significantly higher in non-improved patients, but there were fewer γδT cells compared with those in improved patients. Characterization of 37 cell clusters revealed that the frequency of effector CD8+ T (P = 0.003), CD4+ TCM (P = 0.033), CD4+ TEM (P = 0.039), and inhibitory natural killer (NK) cells (P = 0.029) decreased in HBV-ACLF patients after ALSS therapy. Sub group analyses after treatment showed that the improved patients had higher proportions of CD4+ TCM (P = 0.010), CD4+ TEM (P = 0.021), and γδT cells (P = 0.003) and a lower proportion of monocytes (P = 0.012) compared with the non-improved patients. CONCLUSIONS: Changes in effector CD8+ T cells, effector and memory CD4+ T cells, and inhibitory NK cells are associated with ALSS treatment of HBV-ACLF. Moreover, monocytes and γδT cells exhibited the main differences when patients obtained different prognoses. The phenotypic heterogeneity of lymphocytes and monocytes may contribute to the prognosis of ALSS and future immunotherapy strategies.

Mixed mode of artificial liver support in patients with acute-on-chronic liver failure: a retrospective cohort study.

BACKGROUND AND AIMS: Different modes of artificial liver support (ALS) therapy can improve the survival of patients with acute-on-chronic liver failure (ACLF). This study aimed to compare the effects of mixed using different modes of ALS (MALS) and single using one mode of ALS (SALS) on 28- and 90-day survival rates of ACLF. METHODS: Clinical data and survival times of patients with ACLF treated for ALS between January 1, 2018 and December 30, 2021 were retrospectively collected. Cox regression analysis was performed to identify risk factors of 28- and 90-day mortalities. RESULTS: Of the 462 eligible ACLF patients, 388 belonged to the SALS group (76.3% male, 74.2% cirrhosis) and 74 to the MALS group (86.5% male, 71.6% cirrhosis). Comparison of 28-day and 90-day crude mortality between the SALS and MALS groups showed no significant differences (28-day: 20.4% vs. 14.9%, p = 0.27; 90-day: 44.6% vs. 52.7%, p = 0.20). After adjusting for confounders, the 28-day mortality (adjusted hazard ratio [aHR]: 0.32, 95% confidence interval [CI] 0.16-0.65) and 90-day mortality (aHR: 0.65, 95% CI 0.44-0.95) in the MALS group were significantly lower than those in the SALS group. These associations were consistently observed across pre-specified subgroups according to age, sex, etiology, and Child-Pugh grade. However, positive interactions between MALS and 90-day mortality were found between MALS and 90-day mortality in those with MELD score ≥ 22 and international normalized ratio ≥ 1.9 (p for interaction < 0.05). CONCLUSION: MALS therapy significantly decreased 28- and 90-day mortalities of ACLF than SALS did, especially in advanced stages.

A multi-subgroup predictive model based on clinical parameters and laboratory biomarkers to predict in-hospital outcomes of plasma exchange-centered artificial liver treatment in patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: Postoperative risk stratification is challenging in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) who undergo artificial liver treatment. This study characterizes patients' clinical parameters and laboratory biomarkers with different in-hospital outcomes. The purpose was to establish a multi-subgroup combined predictive model and analyze its predictive capability. Methods: We enrolled HBV-ACLF patients who received plasma exchange (PE)-centered artificial liver support system (ALSS) therapy from May 6, 2017, to April 6, 2022. There were 110 patients who died (the death group) and 110 propensity score-matched patients who achieved satisfactory outcomes (the survivor group). We compared baseline, before ALSS, after ALSS, and change ratios of laboratory biomarkers. Outcome prediction models were established by generalized estimating equations (GEE). The discrimination was assessed using receiver operating characteristic analyses. Calibration plots compared the mean predicted probability and the mean observed outcome. Results: We built a multi-subgroup predictive model (at admission; before ALSS; after ALSS; change ratio) to predict in-hospital outcomes of HBV-ACLF patients who received PE-centered ALSS. There were 110 patients with 363 ALSS sessions who survived and 110 who did not, and 363 ALSS sessions were analyzed. The univariate GEE models revealed that several parameters were independent risk factors. Clinical parameters and laboratory biomarkers were entered into the multivariate GEE model. The discriminative power of the multivariate GEE models was excellent, and calibration showed better agreement between the predicted and observed probabilities than the univariate models. Conclusions: The multi-subgroup combined predictive model generated accurate prognostic information for patients undergoing HBV-ACLF patients who received PE-centered ALSS.

Risk factors of nosocomial infection in patients underwent artificial liver support system: a retrospective case-control study.

BACKGROUND: Although nosocomial infection is one of the most discussed problems in patients undergoing artificial liver support system (ALSS) treatment, only few solutions have been proposed so far. This study aimed to explore the risk factors of nosocomial infection in patients treated with ALSS in order to aid in the development of future preventive measures. METHODS: This retrospective case-control study included patients treated with ALSS at the Department of Infectious Diseases, First Affiliated Hospital of xxx Medical University between January 2016 and December 2021. RESULTS: One hundred seventy-four patients were included. There were 57 patients in the nosocomial infection group and 117 patients in the non-nosocomial infection group, of them 127 males (72.99%) and 47 females (27.01%) with an average age of 48.15 ±â€…14.19 years old. Multivariate logistic regression analysis revealed that total bilirubin [odds ratio (OR) = 1.004; 95% confidence interval (CI), 1.001-1.007; P  = 0.020], number of invasive procedures (OR = 2.161; 95% CI, 1.500-3.313; P  < 0.001), blood transfusion (OR = 2.526; 95% CI, 1.312-4.864; P  = 0.006) were independent risk factors and haemoglobin (Hb) (OR = 0.973; 95% CI, 0.953-0.994; P  = 0.011) was a protective factor for nosocomial infection in patients treated with ALSS. CONCLUSION: The total bilirubin, transfusion of blood products and higher number of invasive operations were independent risk factors for nosocomial infection in patients treated with ALSS, while higher Hb was a protective factor.

Analysis of Efficacy and Safety of Small-Volume-Plasma Artificial Liver Model in the Treatment of Acute-On-Chronic Liver Failure.

To explore the efficacy and safety of a small-volume-plasma artificial liver support system (ALSS) in the treatment of acute-on-chronic liver failure (ACLF). A retrospective analysis was performed. All ACLF patients received ALSS of plasma exchange & double plasma molecular absorb system (PE+DPMAS) treatment, and successfully completed this treatment. Patients were divided into small-volume and half-volume plasma groups. We compared the changes of the indicators on liver function, kidney function, blood coagulation function, and blood ammonia level before and after PE+DPMAS treatment; we compared the short-term and long-term curative effects between small-volume and half-volume plasma groups; and the factors influencing Week 4 and Week 12 mortality of ACLF patients were analyzed. The Week 4 improvement rates were 63.96 % and 66.86 % in the small-volume and half-volume plasma groups, respectively. The Week 12 survival rates in the small-volume-plasma and half-volume plasma groups were 66.72 % and 64.61 %, respectively. We found several risk factors affecting Week 4 and Week 12 mortality. Kaplan-Meier survival curves suggested no significant difference in Week 4 and Week 12 survival rates between the small-volume and half-volume plasma groups (P=0.34). The small-volume-plasma PE+DPMAS treatment could effectively reduce bilirubin and bile acids, and this was an approach with high safety and few complications, similar to the half-volume-plasma PE+DPMAS treatment. The small-volume-plasma PE+DPMAS has the advantage of greatly reducing the need for intraoperative plasma, which is especially of importance in times of shortage of plasma.

[Assessment Value of Short-Term Prognosis of Six Predictive Models for Patients with Acute-on-Chronic Liver Failure Treated with Artificial Liver Support System].

Objective: To apply 6 predictive models on acute-on-chronic liver failure (ACLF) patients treated with artificial liver support system (ALSS), and to compare their assessment values for the short-term prognosis of patients. Methods: A total of 258 ACLF patients who underwent ALSS therapy between January 2018 and December 2019 were selected from the ALSS clinical database established by West China Hospital, Sichuan University, and their clinical data and 90-day prognosis information were collected. Cox proportional hazards model was used to estimate the association between the six predictive models, including Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH ACLF), European Association for the Study of the Liver--Chronic Liver Failure-Consortium (CLIF-C) ACLF, CLIF-C Organ Failure (OF), Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) ACLF, Model for End-Stage Liver Disease (MELD) and Simplified MELD (sMELD), and 90-day mortality, which included death or receiving liver transplantation. The area under the receiver operating characteristic (ROC) curve ( AUC), Harrell's C-index and Brier scores were calculated and compared to evaluate the predictive power. Results: A total of 258 ACLF patients were enrolled. Of these patients, who had a mean age of (46.2±11.7) years old, 37 (14.3%) patients were female, 202 (78.3%) patients had a diagnosis of liver cirrhosis, and 107 (41.5%) patients died during the 90-day follow-up period. The six predictive models all yielded higher scores for patients who died than those for patients who survived (all P<0.001). The six predictive models were all independent risk factors for the short-term prognosis of ACLF patients treated with ALSS (all adjusted hazard ratio [HR]>1, all P<0.001). The AUC (0.806, 95% confidence interval [CI]: 0.753-0.853) and Harrell's C-index (0.772, 95% CI: 0.727-0.816) of COSSH ACLF were much higher than those of the five other predictive models (all AUCs<0.750, P<0.01; all Harrell's C-indices<0.750, P<0.001). The Brier score of COSSH ACLF was 0.18 (95% CI: 0.15-0.20). The 90-day mortality of patients defined as having low risk, moderate risk, and high risk according to the risk stratification of COSSH ACLF were 22.2%, 56.3%, and 90.2%, respectively. Conclusion: The COSSH ACLF could more accurately predict short-term prognosis in ACLF patients who received ALSS therapy, and could facilitate clinical decision-making.

A non-bioartificial liver support system combined with transplantation in HBV-related acute-on-chronic liver failure.

We aim to determine the impact of an artificial liver support system (ALSS) treatment before liver transplantation (LT), and identify the prognostic factors and evaluate the predictive values of the current commonly used ACLF prognostic models for short-term prognosis after LT. Data from 166 patients who underwent LT with acute-on-chronic liver failure (ACLF) were retrospectively collected from January 2011 to December 2018 from the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were divided into two groups depending on whether they received ALSS treatment pre-LT. In the observation group, liver function tests and prognostic scores were significantly lower after ALSS treatment, and the waiting time for a donor liver was significantly longer than that of the control group. Both intraoperative blood loss and period of postoperative ICU care were significantly lower; however, there were no significant differences between groups in terms of total postoperative hospital stays. Postoperative 4-week and 12-week survival rates in the observation group were significantly higher than those of the control group. Similar trends were also observed at 48 and 96 weeks, however, without significant difference. Multivariate Cox regression analysis of the risk factors related to prognosis showed that preoperative ALSS treatment, neutrophil-lymphocyte ratio, and intraoperative blood loss were independent predicting factors for 4-week survival rate after transplantation. ALSS treatment combined with LT in patients with HBV-related ACLF improved short-term survival. ALSS treatment pre-LT is an independent protective factor affecting the 4-week survival rate after LT.

Characterization of an Artificial Liver Support System-Related Vasovagal Reaction.

OBJECTIVE: An artificial liver support system (ALSS) is an effective therapy for patients with severe liver injury. A vasovagal reaction (VVR) is a common complication in various treatment settings but has not been reported previously in ALSS. METHODS: This study retrospectively evaluated patients who suffered an ALSS-related VRR between January 2018 and June 2019. We collected data from VVR episodes including onset time, duration, changes in heart rate (HR) and blood pressure (BP), and drug treatment. RESULTS: Among 637 patients who underwent ALSS treatment, 18 were included in the study. The incidence of VVR was approximately 2.82%. These patients were characterized by a rapid decrease in BP or HR with associated symptoms such as chest distress, nausea, and vomiting. The majority of patients (78%) suffered a VVR during their first ALSS treatment. Sixteen patients (89%) had associated symptoms after treatment began. Sixteen patients (89%) received human albumin or Ringer's solution. Atropine was used in 11 patients (61%). The symptoms were relieved within 20 min in 15 patients and over 20 min in 3 patients. CONCLUSIONS: A VVR is a rare complication in patients with severe liver injury undergoing ALSS treatment. Low BP and HR are the main characteristics of a VVR.

A novel predictive score for citrate accumulation among patients receiving artificial liver support system therapy with regional citrate anticoagulation.

Patients with liver failure may suffer citrate accumulation when using regional citrate anticoagulation for artificial liver support system therapy (RCA-ALSS therapy). This study aimed to develop a predictive scoring system to stratify the risk of citrate accumulation. A total of 338 patients treated with RCA-ALSS therapy were retrospectively enrolled and randomly divided into derivation and validation cohorts. Longer duration of citrate accumulation (LDCA) was defined as the presence of citrate accumulation 2 h after RCA-ALSS therapy. Four baseline variables were found to be independently associated with LDCA: gender, international normalized ratio of prothrombin time, serum creatinine, and serum chloride. A predictive R-CA model and its simplified R-CA score were developed. The R-CA model (AUROC = 0.848) was found to be superior to the MELD score (AUROC = 0.725; p = 0.022) and other univariate predictors (AUROCs < 0.700; all p ≤ 0.001) in predicting LDCA. The R-CA score (AUROC = 0.803) was as capable as the R-CA model (p = 0.369) and the MELD score (p = 0.174), and was superior to other univariate predictors (all p < 0.05) in predicting LDCA. An R-CA score of 0-2 had a negative predictive value of 90.2% for LDCA. Our R-CA score reliably predicts LDCA in patients with RCA-ALSS therapy, and it is easy to use. Patients with R-CA score of 0-2 can safely receive RCA-ALSS therapy, while others should be carefully evaluated before treatment.Trial registration: Chinese Clinical Trial Registry, ChiCTR2000029179. Registered 17 January 2020, https://www.chictr.org.cn/showproj.aspx?proj=48084.

Comparison of plasma exchange, double plasma molecular adsorption system, and their combination in treating acute-on-chronic liver failure.

OBJECTIVE: Our objective was to compare the effectiveness of nonbiological artificial liver (NBAL) support, particularly short-term (28-day) survival rates, in patients who underwent treatment using double plasma molecular adsorption system (DPMAS), plasma exchange (PE), or combined PE+DPMAS, in addition to comprehensive physical treatment for different stages of acute-on-chronic liver failure (ACLF). METHODS: We retrospectively reviewed clinical data of 135 patients with ACLF who received NBAL treatment between November 2015 and February 2019. The patients were categorized into PE, DPMAS, and PE+DPMAS groups. Short-term effectiveness of treatment was assessed and compared based on selected clinical findings, laboratory parameters, and liver function markers. RESULTS: Coagulation function improved significantly in all groups after treatment. In the PE and PE+DPMAS groups, prothrombin time decreased to different degrees, whereas plasma thromboplastin antecedent increased significantly after treatment. White blood cell counts increased and platelet counts decreased in all groups after treatment. The model for end-stage liver disease score, Child-Pugh grade, systematic inflammatory syndrome score, and sepsis-related organ failure score decreased in all three groups after treatment. CONCLUSIONS: PE, DPMAS, and PE+DPMAS improved disease indicators in all patients with ACLF. The combined treatment improved the short-term effectiveness of treatment, especially in patients with mild ACLF.

Effectiveness and Safety Assessment of Citrate Anticoagulation During Albumin Dialysis in Comparison to Other Methods of Anticoagulation.

Liver failure is a serious and often deadly disease often requiring MARS (Molecular Adsorbent Recirculating System) therapy. Choosing the safe and effective method of anticoagulation during artificial liver support systems seems to be very difficult and extremely important. The aim of this study was to assess effectiveness and safety of regional anticoagulation with citrate in liver failure patients during MARS. We used a single center observational study. We analyzed 158 MARS sessions performed in 65 patients: 105 (66.5%) sessions in 41 patients with heparin anticoagulation, 40 (25.3%) sessions in 19 patients with citrate, and 13 (8%) sessions in only five patients without anticoagulation, that were excluded from part of the analysis. To determine the effectiveness of regional anticoagulation with citrate, probability of filter survival and changes in laboratory parameters were analyzed according to the applied method of anticoagulation. The safety of citrate was determined by Ca/Ca2+ ratio, acid-base balance, bleeding complications, and the need for blood product transfusions. The probability of filter survival in the citrate group was 94% and in the heparin group 82% (P = 0.204). There was no relationship between the method of anticoagulation and effectiveness of MARS therapy in lowering the levels of the analyzed parameters. Only one patient had a Ca/Ca2+ ratio higher than he safety margin. There were no statistically significant changes in pH and lactate level irrespective of anticoagulation; bicarbonate dropped significantly only in the heparin group (P = 0.03). The frequency of bleeding complications and the need for transfusions did not differ significantly between groups. Regional anticoagulation with citrate can be an effective and safe method of anticoagulation during MARS therapy, but requires attentive monitoring and further studies in liver failure patients.

Current Evidence for Extracorporeal Liver Support Systems in Acute Liver Failure and Acute-on-Chronic Liver Failure.

Artificial (nonbiological) extracorporeal liver support devices aim to remove albumin-bound and water-soluble toxins to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while hepatic recovery or liver transplant occurs. The following beneficial effects have been documented: improvement of jaundice, amelioration of hemodynamic instability, reduction of portal hypertension, and improvement of hepatic encephalopathy. The only randomized prospective multicenter controlled trial to show an improvement in transplant-free survival was for high-volume plasmapheresis. Biological (cell-based) extracorporeal liver support systems aim to support the failing liver through detoxification and synthetic function and warrant further study for safety and benefit.

Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-on-chronic liver failure: a nationwide prospective multicenter study in China.

BACKGROUND: Plasma exchange (PE)-centered artificial liver support system reduced the high mortality rate of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). But the data were diverse in different medical centers. The present prospective nationwide study was to evaluate the effects of PE on patients with HBV-ACLF at different stages. METHODS: From December 2009 to December 2011, we evaluated 250 patients at different stages of HBV-ACLF from 10 major medical centers in China. All the laboratory parameters were collected at admission, before and after PE. RESULTS: Among the 250 patients who underwent 661 rounds of PE, one-month survival rate was 61.6%; 141 (56.4%) showed improvement after PE. Variables such as age (P=0.000), levels of total bilirubin (TB, P=0.000), direct bilirubin (P=0.000), total triglycerides (P=0.000), low-density lipoprotein (P=0.022), Na+ (P=0.014), Cl- (P=0.038), creatinine (Cr, P=0.007), fibrinogen (P=0.000), prothrombin time (PT, P=0.000), white blood cell (P=0.000), platelet (P=0.003) and MELD (P=0.000) were significantly related to prognosis. Multivariate logistic regression analysis showed that age, disease stage, TB, Cr and PT levels were independent risk factors of mortality among HBV-ACLF patients. CONCLUSIONS: PE can improve the clinical outcome of patients with HBV-ACLF. Levels of TB, Cr and PT, age and disease stage help to predict prognosis.

Hepatic Encephalopathy: Pharmacological Therapies Targeting Ammonia.

Hepatic encephalopathy (HE) is a major complication in patients with decompensated cirrhosis, leading to higher readmission rates causing a profound burden of disease and considerable health care costs. Because ammonia is thought to play a crucial role in the pathogenesis of HE, therapies directed at reducing ammonia levels are now being aggressively developed. Ammonia scavengers such as AST-120 (spherical carbon adsorbent), glycerol phenylbutyrate, sodium phenylacetate or sodium benzoate, and ornithine phenylacetate have been used to improve HE symptoms. A new approach, bowel cleansing with polyethylene glycol 3350, appears to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt HE (at 24 hours after treatment) than lactulose. Extracorporeal devices, although now used primarily in research settings, have also been utilized in patients with refractory HE, but are not approved for clinical management.

Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is increasingly recognized as a distinct clinical entity and is associated with a high short-term mortality. The most common cause of ACLF is chronic hepatitis B worldwide. Currently, there is no standardized approach for the management of ACLF and the efficacy and safety of therapeutic modalities are uncertain. DATA SOURCES: PubMed and Web of Science were searched for English-language articles. The search criteria focused on clinical trials and observational studies on the treatment of patients with HBV-related ACLF. RESULTS: Therapeutic approaches for ACLF in patients with chronic hepatitis B included nucleos(t)ide analogues, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation. All of these therapeutic approaches have shown the potential to improve liver function and increase patients' survival rate, but most of the studies were not randomized or controlled. CONCLUSION: Substantial challenges for the treatment of HBV-related ACLF remain and further basic research and randomized controlled clinical trials are needed.

Safety of Human Hepatoma Cell-Line Constructing Bioartificial Liver Supporting System Treating Patients with Liver Failure.

BACKGROUND/AIMS: To observe the clinical safety of bioartificial liver supporting system constructed by human hepatoma cell line. METHODOLOGY: Seventeen patients with liver failure were treated with C3A-cell-constructed bioartificial liver supporting system, contrasting the difference of biochemical results and imaging data with 9 patients treated with non-bioartificial liver during 5-year treatment. RESULTS: 11 cases of Treatment Group survived at 3 months' follow-up, among whom 2 cases underwent hepatic transplantation. 9 cases without hepatic transplantation survived in 5-year follow-up, and 1 of them was found to occur focal liver lesion at the 5th years, and had hepatic lobectomy. Pathological prompt: hepatocellular carcinoma with moderate differentiation. Totally 4 patients in Control Group survived after 3 months' follow-up, including 1 patient of hepatic transplantation. All the 3 patients without hepatic transplantation survived the last 5-year follow-up, with basically normal biochemical indicators and no focal liver lesion were found by imaging examination. CONCLUSIONS: It was safe to use bioartificial liver constructed by tumor cell line C3A to treat liver failure.

Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: a randomized, controlled trial.

BACKGROUND: Albumin dialysis with the Molecular Adsorbent Recirculating System (MARS) (Gambro, Lund, Sweden), a noncell artificial liver support device, may be beneficial in acute liver failure (ALF). OBJECTIVE: To determine whether MARS improves survival in ALF. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov: NCT00224705). SETTING: 16 French liver transplantation centers. PATIENTS: 102 patients with ALF. INTERVENTION: Conventional treatment (n = 49) or MARS with conventional treatment (n = 53), stratified according to whether paracetamol caused ALF. MEASUREMENTS: 6-month survival and secondary end points, including adverse events. RESULTS: 102 patients (mean age, 40.4 years [SD, 13]) were in the modified intention-to-treat (mITT) population. The per-protocol analysis (49 conventional, 39 MARS) included patients with at least 1 session of MARS of 5 hours or more. Six-month survival was 75.5% (95% CI, 60.8% to 86.2%) with conventional treatment and 84.9% (CI, 71.9% to 92.8%) with MARS (P = 0.28) in the mITT population and 75.5% (CI, 60.8% to 86.2%) with conventional treatment and 82.9% (CI, 65.9% to 91.9%) with MARS (P = 0.50) in the per-protocol population. In patients with paracetamol-related ALF, the 6-month survival rate was 68.4% (CI, 43.5% to 86.4%) with conventional treatment and 85.0% (CI, 61.1% to 96.0%) with MARS (P = 0.46) in the mITT population. Sixty-six of 102 patients had transplantation (41.0% among paracetamol-induced ALF; 79.4% among non-paracetamol-induced ALF) (P < 0.001). Adverse events did not significantly differ between groups. LIMITATION: The short delay from randomization to liver transplantation (median, 16.2 hours) precludes definitive efficacy or safety evaluations. CONCLUSION: This randomized trial of MARS in patients with ALF was unable to provide definitive efficacy or safety conclusions because many patients had transplantation before administration of the intervention. Acute liver failure not caused by paracetamol was associated with greater 6-month patient survival. PRIMARY FUNDING SOURCE: Assistance Publique-Hôpitaux de Paris.

Artificial liver support system combined with liver transplantation in the treatment of patients with acute-on-chronic liver failure.

BACKGROUND: The search for a strategy to provide temporary liver support and salvage the patients with acute-on-chronic liver failure (ACLF) remains an important issue. This study was designed to evaluate the experience in artificial liver support system (ALSS) combined with liver transplantation (LT) in the treatment of ACLF. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and seventy one patients with HBV related ACLF undergoing LT between January 2001 and December 2009 were included. Of the 171 patients, 115 received 247 sessions of plasma exchange-centered ALSS treatment prior to LT (ALSS-LT group) and the other 56 received emergency LT (LT group). The MELD score were 31±6 and 30±7 in ALSS-LT group and LT group. ALSS treatment resulted in improvement of liver function and better tolerance to LT. The average level of serum total bilirubin before LT was lower than that before the first time of ALSS treatment. The median waiting time for a donor liver was 12 days (2-226 days) from the first run of ALSS treatment to LT. Compared to LT group, the beneficial influences of ALSS on intraoperative blood loss and endotracheal intubation time were also observed in ALSS-LT group. The 1-year and 5-year survival rates in the ALSS-LT group and LT group were 79.2% and 83%, 69.7% and 78.6%. CONCLUSIONS/SIGNIFICANCE: Plasma exchange-centered ALSS is beneficial in salvaging patients with ACLF when a donor liver is not available. The consequential LT is the fundamental treatment modality to rescue these patients and lead to a similar survival rate as those patients receiving emergency transplantation.

Key challenges to the development of extracorporeal bioartificial liver support systems.

BACKGROUND: For nearly three decades, extracorporeal bioartificial liver (BAL) support systems have been anticipated as promising tools for the treatment of liver failure. However, these systems are still far from clinical application. This review aimed to analyze the key challenges to the development of BALs. DATA SOURCE: We carried out a PubMed search of English-language articles relevant to extracorporeal BAL support systems and liver failure. RESULTS: Extracorporeal BALs face a series of challenges. First, an appropriate cell source for BAL is not readily available. Second, existing bioreactors do not provide in vivo-like oxygenation and bile secretion. Third, emergency needs cannot be met by current BALs. Finally, the effectiveness of BALs, either in animals or in patients, has been difficult to document. CONCLUSIONS: Extracorporeal BAL support systems are mainly challenged by incompetent cell sources and flawed bioreactors. To advance this technology, future research is needed to provide more insights into interpreting the conditions for hepatocyte differentiation and liver microstructure formation.

Factors influencing the transfer of porcine endogenous retroviruses across the membrane in bioartificial livers.

OBJECTIVES: to investigate the factors influencing the transfer of porcine endogenous retroviruses (PERVs) across the membrane in a new bioartificial liver (BAL). METHODS: A new BAL containing 2 circuits was constructed using plasma component separators with membrane pore sizes of 10 nm, 20 nm, 30 nm, and 35 nm, or a plasma filter with a membrane pore size of 500 nm. Cocultured cells of porcine hepatocytes and mesenchymal stem cells or single porcine hepatocytes were incubated in the bioreactors, and the BAL worked for 72 hours, with supernatant samples in internal and external circuits collected every 12 hours. PERV RNA, reverse transcriptase (RT) activity, and in vitro infectivity of the supernatant were detected. RESULTS: With the plasma filters, the results of PERV detection were the same in both circuits. With plasma component separators, PERV RNA was found in the external circuits, but no positive RT activity or HEK293 cell infection was found. The time at which the PERV RNA was first detected varied with the pore size of membrane; the larger the membrane pore size was, the earlier the RNA was detected. The PERV RNA level in the external circuits was reduced significantly compared with that in the internal circuits at any detecting time. CONCLUSIONS: The plasma component separators with membrane pore size =35 nm could significantly reduce the passage of infectious PERVs. And the membrane pore size, the treatment duration, and the viral level in the internal circuit were potential factors influencing the transfer of PERVs across the membrane in a BAL. In addition, a low risk of PERV transmission from porcine hepatocytes to human cells was found.