A novel stem cell therapy for hepatitis B virus-related acute-on-chronic liver failure.

The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.

A novel stem cell therapy for hepatitis B virus-related acute-on-chronic liver failure

The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.

Adverse events of benralizumab in moderate to severe eosinophilic asthma: A meta-analysis.

BACKGROUND: Benralizumab, a humanized, anti-interleukin-5 (anti-IL-5) receptor α monoclonal antibody that directly and rapidly depletes eosinophils, has shown significant efficacy in reducing asthma exacerbations and improving lung function in moderate to severe eosinophilic asthma patients. However, there is some controversy regarding the adverse events (AEs) of benralizumab and a comprehensive analysis of these AEs has not been performed. This study aimed to assess the incidence of these AEs in published randomized controlled trials (RCTs). METHODS: We searched for RCTs in the Embase, PubMed and Cochrane databases that compared benralizumab with placebo in moderate to severe eosinophilic asthma patients. The outcome was the incidence of AEs during the observation period. RESULTS: Eight RCTs were analyzed in this study. Patients treated with benralizumab had a lower risk of overall AEs (risk ratio (RR) 0.94; 95% confidence interval (CI) 0.90-0.98), serious adverse events (SAEs) (RR 0.82; 95% CI 0.68-0.98), asthma exacerbation (RR 0.72, 95% CI 0.61-0.85), bronchitis (RR 0.76, 95% CI 0.59-0.96) and sinusitis (RR 0.64, 95% CI 0.48-0.85), but had a higher risk of headache (RR 1.42, 95% CI 1.07-1.87) and pyrexia (RR 2.26, 95% CI 1.32-3.87) than patients treated with placebo. No increased incidence of death, hypersensitivity, injection-site reactions, nasopharyngitis, rhinitis, upper respiratory tract infection, influenza, cough, nausea, back pain or arthralgia was observed with benralizumab compared with placebo. CONCLUSIONS: Benralizumab reduced the risk of SAEs, asthma exacerbation, bronchitis and sinusitis, and aggravated the risk of headache and pyrexia. Other AEs were comparable between the benralizumab group and placebo group. Therefore, benralizumab is a relatively safe drug, but vigilance regarding AEs is imperative during long-term treatment.

[Clinical characteristics of 4132 patients with alcoholic liver disease].

OBJECTIVE: To study the clinical characteristics of patients with alcoholic liver disease (ALD). METHODS: The records of the 302 Hospital of People's Liberation Army (Beijing, China) were searched to identify patients diagnosed with liver disease for retrospective analysis of ALD. Measurement data was summarized as mean +/- standard deviation and intergroup comparisons were made using ANOVA; count data was assessed using the chi-square test. RESULTS: Among the total 4132 ALD cases, 97.68% were male and 2.32% were female; ages ranged from 18 to 95 years-old,with the average age being 48.11+/-10.58 years and the range of 40 to 60 years-old being the most frequently represented.Considering all patients with liver disease from 2003 to 2012,ALD cases increased over time (from 2.00% in 2003 to 5.05% in 2012). The overall ALD cases were represented by alcoholic cirrhosis (70.35%), alcoholic hepatitis (19.26%), alcoholic fatty liver (6.29%), and alcoholic liver failure (4.09%). Among the ALD patients between 40 and 60 years of age, 73.81% had cirrhosis,compared to 50.42% of ALD patients less than 40 years-old (P less than 0.001). Comparison of ALD cases in 5-year increments showed increasing trends in rates of alcoholic cirrhosis and alcoholic hepatic failure;moreover, there was an increasing annual trend in the percentage of alcoholic liver failure cases among the total cases of liver failure in our hospital. CONCLUSION: From 2003 to 2012,our hospital admissions increased for patients with alcoholic liver disease, and the patients were primarily in the age range of 40-60 years-old. In general, incidences of alcoholic liver failure and cirrhosis increased in recent years, and cirrhosis has been common among the elderly patients with ALD.

[The value of the baseline MELD scores, MELD-Na scores and iMELD scores in short-term prognosis in hepatitis B virus related acute-on-chronic liver failure patients].

OBJECTIVE: To explore the function of the baseline model for end-stage liver disease (MELD) scores, MELD-Na scores and iMELD scores in short-term prognosis in the initial treatment of hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) patients. METHODS: 232 HBV-related ACLF patients who received initial treatment in 302 Military Hospital of China from January 2011 to January 2013 were enrolled in this prospective clinical follow-up. The relationship between the baseline MELD scores, MELD-Na scores, iMELD scores and clinical outcomes were analyzed, and the value of these three models for short term prognosis was assessed. RESULTS: Finally the 12-week clinical follow-up was completed in 191 patients, with the completion rate of 82.33%. Eighty-five patients died, with the fatality rate of 44.50%. Compared with the survival group, in non-survival group, the baseline of MELD scores (26.65 ± 7.75 vs. 21.19 ± 5.42, t=-5.720, P=0.000), MELD-Na scores (29.16 ± 11.35 vs. 21.72 ± 6.33, t=-5.729, P=0.000), iMELD scores (47.19 ± 10.96 vs. 38.02 ± 7.01, t=-7.011, P=0.000), total bilirubin (TBil: 374.3 ± 150.1 µmol/L vs. 305.5 ± 147.1 µmol/L, t=-3.182, P=0.002), creatinine (Cr: 110.7 ± 90.1 µmol/L vs. 71.1 ± 35.1 µmol/L, t=-4.157, P=0.000) and international normalized ratio (INR: 2.3 ± 0.9 vs. 2.0 ± 0.6, t=-2.754, P=0.006) were significantly increased, but the baseline of serum Na⁺ (132.8 ± 6.1 mmol/L vs. 136.7 ± 5.1 mmol/L, t=4.861, P=0.000) was significantly lowered. It was shown by Spearman correlation analysis that the baseline MELD scores, MELD-Na scores and iMELD scores all had positive correlation with the short-term prognosis of patients (r value was 0.398, 0.404, and 0.470, respectively, all P=0.000), the baseline of serum Na⁺ had a negative correlation with the short-term prognosis of patients (r=-0.365, P=0.000). It was shown by receiver operating characteristic curve (ROC curve) that the cut-off scores of the baseline of MELD scores, MELD-Na scores and iMELD scores were 25.07, 25.43 and 43.11 respectively, and the area under ROC curve (AUC) of the baseline of MELD scores, MELD-Na scores and iMELD scores were 0.731, 0.735 and 0.773, respectively. The sensitivity of the three models was 55.3%, 57.7%, 63.5%, and the specificity was 84.9%, 84.0%, 84.9% respectively. The value of the three models had no difference in short-term prognostic prediction. According to the respective cut-off score, the three prediction models were divided into four groups, and all of them had differences in fatality rate on the whole (χ² for MELD scores was 34.740, P=0.000; χ² for MELD-Na scores was 36.861, P=0.000; χ² for iMELD scores was 50.127, P=0.000). The mortality was elevated gradually as the equation scores increased. CONCLUSIONS: The baseline of MELD scores, MELD-Na scores and iMELD scores can predict well the short-term prognosis of the initial treatment in HBV-related ACLF patients, and have relatively good clinical value for guiding therapy.

Newly established human liver cell line: a potential cell source for the bioartificial liver in the future.

The clinical use of a bioartificial liver (BAL) device strongly depends on the development of human liver cell lines. The aim of this study was to establish and assess the potential use of the stable HepG2 cell line expressing human augmenter of liver regeneration (hALR). The cDNA encoding hALR protein was inserted into pcDNA3.1 to generate pcDNA3.1/hALR, following which pcDNA3.1/hALR was transfected to HepG2 to establish a cell line that stably expressed hALR (HepG2 hALR). A total of 800 million HepG2 hALR cells were loaded into laboratory-scale BAL bioreactors and cultured for 4 days, during which time the parameters of hepatocyte-specific function and general metabolism were determined. The cell line that stably expressed human ALR was successfully established. The expression of recombinant hALR was higher in the HepG2 hALR cell line than in the HepG2 cell line based on immunofluorescence and immunoblot assays. In samples removed from the BAL bioreactor on day 4, compared to HepG2 cells, HepG2 hALR cells produced significantly more alpha-fetoprotein (127.3 %; P < 0.05) and urea (128.8 %; P < 0.05) and eliminated more glucose (135.7 %; P < 0.05); the level of human albumin was also higher (117 %) in HepG2 hALR cells, but the difference was not significant (P > 0.05). After 24 h of culture, the mean lidocaine removal rate was 65.1 and 57.3 % in culture supernatants of HepG2 hALR and HepG2 cell lines, respectively (P < 0.01). Based on these results, we conclude that HepG2 hALR cells showed liver-specific functionality when cultured inside the bioreactor and would therefore be a potential cell source for BAL.

[Clinical study on hybrid bioartificial liver supporting system for acute on chronic liver failure patients].

OBJECTIVE: To construct an hybrid bioartificial liver supporting system, and observe its effectiveness and safety on patients with acute on chronic liver failure. METHODS: Hybrid bioartificial liver supporting system (HBALSS) was constructed using bioreactor with HepG2 cells transfected with human augmenter of liver regeneration (hALR) gene. 12 acute on chronic liver failure patients were divided into 2 groups randomly. The treatment group was treated with the hybrid bioartificial liver support system. The group underwent plasma exchange was used as control. RESULTS: In the treatment group, four patients recovered, one patient died of hepatic encephalopathy, one patient died of hepatorenal syndrome, one patient recovered, but died of gastrointestnal bleeding after 1 year. In control group, two patients recovered, one patient underwent orthotropic liver transplantation, and three patients died of liver failure. CONCLUSION: The hybrid bioartificial liver supporting system with HepG2 cell line was established successfully and have certain safety and effectiveness on acute on chronic liver failure patients.

[Construction and experimental study on off-line hybrid bioartificial liver supporting system with human liver cell line].

OBJECTIVE: To construct an off-line hybrid bioartificial liver supporting system with human liver cell line, and study it's effect on the plasma from patients with liver failure. METHODS: We established the bioreactor using Psu-2s (Fresenius) cultured with Hep G2 cell transfected with human augmenter of liver regeneration (hALR) gene, then constructed a hybrid bioartificial liver supporting system, at last using the bioartificial liver support system to purify the plasma treated 2 hours with serum bilirubin absorbent, separated from acute on chronic liver failure patients infected by hepatitis B virus. RESULTS: Bioreactor was successful constructed. The cell viability in perigastrum of bioreactor is 85.2% and cell propagated rapidly. Before and after treating with bilirubin absorbent, serum total bilirubin was (176.19 +/- 54.14) micromol/L and (50.1 +/- 16.85) micromol/L respectively (P = 0.0002). While there were no significance difference in the level of albumin, urea and glucose. At the begin and end of treatment with bioartificial liver, serum total bilirubin was (50.10 +/- 16.85) micromol/L and (30.27 +/- 15.02) micromol/L respectively (P = 0.000), the urea and albumin increased, urea has significantly difference, but the change of albumin hasn't. CONCLUSION: The off-line hybrid bioartificial liver supporting system with human liver cell line were builded successfully and have synthesis and metabolism functions for acute on chronic liver failure patients.