Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. AIM: To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. METHODS: A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. RESULTS: The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. CONCLUSION: The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.

Clinical Manifestations of Hepatitis E.

The clinical manifestations of hepatitis E are similar to those of other types of viral hepatitis. While acute hepatitis E is usually self-limited, pregnant women and chronic liver disease patients suffering from acute hepatitis E usually present with severe clinical manifestations that may develop into fulminant hepatic failure. Chronic HEV infection is typically seen in organ transplant patients; most HEV cases are asymptomatic and rarely display jaundice, fatigue, abdominal pain, fever, fatigue, or ascites. The clinical manifestations of HEV infection in neonates are diverse and have varied clinical signs, biochemistry, and virus-biomarkers. Lastly, the extrahepatic manifestations and complications of hepatitis E are in need of further study.

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: The changes in liver stiffness measurement (LSM) are unreliable to estimate regression of fibrosis during antiviral treatment for chronic hepatitis B (CHB) patients. The age-male-albumin-bilirubin-platelets score (aMAP), as an accurate hepatocellular carcinoma risk score, may reflect the liver fibrosis stage. Here, we aimed to evaluate the performance of aMAP for diagnosing liver fibrosis in CHB patients with or without treatment. METHODS: A total of 2053 patients from 2 real-world cohorts and 2 multicentric randomized controlled trials in China were enrolled, among which 2053 CHB patients were included in the cross-sectional analysis, and 889 CHB patients with paired liver biopsies before and after 72 or 104 weeks of treatment were included in the longitudinal analysis. RESULTS: In the cross-sectional analysis, the areas under the receiver operating characteristic curve of aMAP in diagnosing cirrhosis and advanced fibrosis were 0.788 and 0.757, which were comparable with or significantly higher than those of the fibrosis index based on 4 factors and the aspartate aminotransferase-platelet ratio. The stepwise approach using aMAP and LSM further improved performance in detecting cirrhosis and advanced fibrosis with the smallest uncertainty area (29.7% and 46.2%, respectively) and high accuracy (82.3% and 79.8%, respectively). In the longitudinal analysis, we established a novel model (aMAP-LSM model) by calculating aMAP and LSM results before and after treatment, which had satisfactory performance in diagnosing cirrhosis and advanced fibrosis after treatment (area under the receiver operating characteristic curve, 0.839 and 0.840, respectively), especially for those with a significant decrease in LSM after treatment (vs LSM alone, 0.828 vs 0.748; P < .001 [cirrhosis]; 0.825 vs 0.750; P < .001 [advanced fibrosis]). CONCLUSIONS: The aMAP score is a promising noninvasive tool for diagnosing fibrosis in CHB patients. The aMAP-LSM model could accurately estimate fibrosis stage for treated CHB patients.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Predicting the Onset of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with rapid progression. This study aimed to develop and validate a prognostic score to predict the onset of ACLF in hepatitis B virus (HBV) etiology. METHODS: The prospective clinical data of 1373 patients with acute deterioration of HBV-related chronic liver disease were used to identify clinical characteristics and develop a prognostic score for the onset of ACLF. RESULTS: Of the patients assessed using the Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF criteria, 903 patients with non-ACLF at admission (1 received transplantation at 5 days) were stratified: 71 with progression to ACLF and 831 without progression to ACLF at 7 days. Four predictors (total bilirubin, international normalized ratio, alanine aminotransferase, and ferritin) were associated significantly with ACLF onset at 7 days. The COSSH-onset-ACLF score was constituted as follows: (0.101 × ln [alanine aminotransferase] + 0.819 × ln [total bilirubin] + 2.820 × ln [international normalized ratio] + 0.016 × ln [ferritin]). The C-indexes of the new score for 7-/14-/28-day onset (0.928/0.925/0.913) were significantly higher than those of 5 other scores (Chronic Liver Failure Consortium ACLF development score/Model for End-stage Liver Disease score/Model for End-stage Liver Disease sodium score/COSSH-ACLF score/Chronic liver failure Consortium ACLF score; all P < .001). The improvement in predictive errors, time-dependent receiver operating characteristic, probability density function evaluation, and calibration curves of the new score showed the highest predictive value for ACLF onset at 7/14/28 days. Risk stratification of the new score showed 2 strata with high and low risk (≥6.3/<6.3) of ACLF onset. The external validation group further confirmed the earlier results. CONCLUSIONS: A new prognostic score based on 4 predictors can accurately predict the 7-/14-/28-day onset of ACLF in patients with acute deterioration of HBV-related chronic liver disease and might be used to guide clinical management.

Development of a Widely Applicable and Simple Prognostic Score for Patients with Acute-on-chronic Liver Failure.

Background and Aims: Acute-on-chronic liver failure (ACLF) tends to progress rapidly with high short-term mortality. We aimed to create a widely applicable, simple prognostic (WASP) score for ACLF patients. Methods: A retrospective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to develop the new score. A prospective longitudinal cohort was recruited for further validation. Results: A total of 541 cases were included in the training set, and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table. In the validation set of 671 cases, WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognostic scores at baseline, day 3, week 1, and week 2. The predictive efficacy and clinical validity of the model improved over time. Patients were assigned to low-, intermediate-, and high-risk groups by their WASP-ACLF scores. Compared with the other two groups, intermediate-risk patients had a more uncertain prognosis, with a 90-day mortality of 44.4-50.6%. Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was <20% for patients with a ≥2 point decrease in WASP-ACLF and was up to 56% for patients with a ≥2 points increase. Similar results were observed in prospective data. Conclusions: The new ACLF prognostic score was simple, widely applicable, and had good predictive efficacy. Continuous assessments and trend of change in WASP-ACLF need to be considered, especially for intermediate-risk patients.

Hepatitis B-related acute-on-chronic liver failure induced by hepatotropic viral insult is associated with worse prognosis than that induced by non-virus insult.

BACKGROUND: The manifestations and prognoses of acute-on-chronic liver failure (ACLF) with different precipitating events remain heterogeneous. We aimed to investigate the characteristics and prognosis of patients with hepatotropic viral insult (HVI)-induced hepatitis B-related ACLF (HBV-ACLF). METHODS: 452 patients with confirmed diagnosis of ACLF were screened in three medical centers in China, and 203 HBV-ACLF patients with definite acute precipitating events were retrospectively analyzed. According to the precipitating events, HBV-ACLF patients induced by HBV reactivation and super-infection with HAV were classified as the hepatotropic viral insult group and those induced by other factors, as the non-virus insult (NVI) group. The clinical characteristics, predictive scoring model, and prognosis of the two groups were compared. RESULTS: Hepatitis B virus reactivation accounted for the largest proportion (39.9%) among all precipitating events. Exacerbation time frame of the HVI group was significantly longer than that of the NVI group (20 days vs. 10 days, P < 0.001). Comparison of intergroup prognosis showed that there was no significant difference in the 28 day mortality (20.9 vs. 13.7%, P = 0.125), while the 90 day and 1 year mortality in the HVI group were higher than those in the NVI group (36.3 vs. 24.4%, P = 0.014; 39.5% vs. 27.5%, P = 0.020, respectively). In the HVI group, the lactic acid-free APASL-ACLF Research Consortium (AARC) had better predictive value for 90 day mortality (0.741). CONCLUSIONS: The 90 day and 1 year survival rate was lower in HBV-ACLF patients induced by HVI than by NVI. The lactate-free AARC score was a better predictor of short- and long-term prognosis in patients with HVI-induced HBV-ACLF.

Clinical Course and Outcome Patterns of Acute-on-chronic Liver Failure: A Multicenter Retrospective Cohort Study.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is acute decompensation of liver function in the setting of chronic liver disease, and characterized by high short-term mortality. In this study, we sought to investigate the clinical course of patients at specific time points, and to propose dynamic prognostic criteria. METHODS: We assessed the clinical course of 453 patients with ACLF during a 12-week follow-up period in this retrospective multicenter study. The clinical course of patients was defined as disease recovery, improvement, worsening or steady patterns based on the variation tendency in prothrombin activity (PTA) and total bilirubin (TB) at different time points. RESULTS: Resolution of PTA was observed in 231 patients (51%) at 12 weeks after the diagnosis of ACLF. Among the remaining patients, 66 (14.6%) showed improvement and 156 (34.4%) showed a steady or worsening course. In patients with resolved PTA, the clinical course of TB exhibited resolved pattern in 95.2%, improved in 3.9%, and steady or worse in 0.8%. Correspondingly, in patients with improved PTA, these values for TB were 28.8%, 27.3%, and 43.9%, respectively. In patients with steady or worsening PTA, these values for TB were 5.7%, 32.3%, and 65.6%, respectively. Dynamic prognostic criteria were developed by combining the clinical course of PTA/TB and the clinical outcomes at 4 and 12 weeks after diagnosis in ACLF patients. CONCLUSIONS: We propose the following dynamic prognostic criteria: rapid progression, slow progression, rapid recovery, slow recovery, and slow persistence, which lay the foundation for precise prediction of prognosis and the improvement of ACLF therapy.

Acute-On-Chronic Liver Failure Defined by Asian Pacific Association for the Study of the Liver Should Include Decompensated Cirrhosis.

Background and Aims: Acute-on-chronic liver failure (ACLF) is an acute deterioration of chronic liver disease with high short-term mortality. The inclusion or exclusion of previously decompensated cirrhosis (DC) in the diagnostic criteria of ACLF defined by the Asian Pacific Association for the Study of the Liver (APASL-ACLF) has not been conclusive. We aimed to evaluate the prognostic impact of decompensated cirrhosis in ACLF. Methods: We retrospectively collected a cohort of patients with a diagnosis of APASL-ACLF (with or without DC) hospitalized from 2012 to 2020 at three liver units in tertiary hospitals. Baseline characteristics and survival data at 28, 90, 180, 360, 540, and 720 days were collected. Results: Of the patients assessed using APASL-ACLF criteria without the diagnostic indicator of chronic liver disease, 689 patients were diagnosed with ACLF, of whom 435 had no decompensated cirrhosis (non-DC-ACLF) and 254 had previously decompensated cirrhosis (DC-ACLF). The 28-, 90-, 180-, 360-, 540-, and 720-day mortality were 24.8, 42.9, 48.7, 57.3, 63.4, and 68.1%, respectively, in DC-ACLF patients, which were significantly higher than in non-DC-ACLF patients (p < 0.05). DC was independently associated with long-term (180/360/540/720 days) but not short-term (28/90 days) mortality in patients with ACLF. Age, total bilirubin, international normalized ratio, and hepatic encephalopathy were independent risk factors for short- and long-term mortality risk in ACLF patients (p < 0.05). Conclusions: Patients with DC-ACLF have a higher mortality rate, especially long-term mortality, compared to non-DC-ACLF patients. Therefore, DC should be included in the diagnostic criteria of APASL-ACLF and treated according to the ACLF management process.

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4.

Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3'UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND & AIMS: Early determination of the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to guide clinical management and decrease mortality. The aim of this study was to develop a new simplified prognostic score to accurately predict outcomes in patients with HBV-ACLF. METHODS: Prospective clinical data from 2,409 hospitalized patients with acute deterioration of HBV-related chronic liver disease were used to develop a new prognostic score that was validated in an external group. RESULTS: A total of 954 enrolled patients with HBV-ACLF were diagnosed based on the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria. Six predictive factors were significantly related to 28-day mortality and constituted a new prognostic score (=1.649×ln(international normalized ratio)+0.457×hepatic encephalopathy score+0.425×ln(neutrophil)+0.396×ln(total bilirubin)+0.576×ln(serum urea)+0.033×age). The C-indices of the new score for 28-/90-day mortality (0.826/0.809) were significantly higher than those of 4 other scores (COSSH-ACLF, 0.793/0.784; CLIF-C ACLF, 0.792/0.770; MELD, 0.731/0.727; MELD-Na, 0.730/0.726; all p <0.05). The prediction error rates of the new score for 28-day mortality were significantly lower than those of the 4 other scores: COSSH-ACLF (15.9%), CLIF-C ACLF (16.3%), MELD (35.3%) and MELD-Na (35.6%). The probability density function evaluation and risk stratification of the new score also showed the highest predictive values for mortality. These results were then validated in an external cohort. CONCLUSION: A new prognostic score based on 6 predictors, without an assessment of organ failure, can accurately predict short-term mortality in patients with HBV-ACLF and might be used to guide clinical management. LAY SUMMARY: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome that is associated with a high short-term mortality rate. We developed a simplified prognostic score for patients suffering from this condition based on a prospective multicentre cohort. This new score had better predictive ability than 4 other commonly used scores.

A dynamic prediction model for prognosis of acute-on-chronic liver failure based on the trend of clinical indicators.

Acute-on-chronic liver failure (ACLF) is a dynamic syndrome, and sequential assessments can reflect its prognosis more accurately. Our aim was to build and validate a new scoring system to predict short-term prognosis using baseline and dynamic data in ACLF. We conducted a retrospective cohort analysis of patients with ACLF from three different hospitals in China. To construct the model, we analyzed a training set of 541 patients from two hospitals. The model's performance was evaluated in a validation set of 130 patients from another center. In the training set, multivariate Cox regression analysis revealed that age, WGO type, basic etiology, total bilirubin, creatinine, prothrombin activity, and hepatic encephalopathy stage were all independent prognostic factors in ACLF. We designed a dynamic trend score table based on the changing trends of these indicators. Furthermore, a logistic prediction model (DP-ACLF) was constructed by combining the sum of dynamic trend scores and baseline prognostic parameters. All prognostic scores were calculated based on the clinical data of patients at the third day, first week, and second week after admission, respectively, and were correlated with the 90-day prognosis by ROC analysis. Comparative analysis showed that the AUC value for DP-ACLF was higher than for other prognostic scores, including Child-Turcotte-Pugh, MELD, MELD-Na, CLIF-SOFA, CLIF-C ACLF, and COSSH-ACLF. The new scoring model, which combined baseline characteristics and dynamic changes in clinical indicators to predict the course of ACLF, showed a better prognostic ability than current scoring systems. Prospective studies are needed to validate these results.

Metabolomic profiles of breath odor compounds for prognostic prediction in patients with acute-on-chronic liver failure: A pilot study.

AIM: The aim of this study was to use a metabonomics approach to identify potential biomarkers of exhaled breath condensate (EBC) for predicting the prognosis of acute-on-chronic liver failure (ACLF). METHODS: Using liquid chromatography mass spectrometry, EBC metabolites of ACLF patients surviving without liver transplantation (n = 57) and those with worse outcomes (n = 45), and controls (n = 15) were profiled from a specialized liver disease center in Beijing. The metabolites were used to identify candidate biomarkers, and the predicted performance of potential biomarkers was tested. RESULTS: Forty-one metabolites, involving glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, and amino acid metabolism, as candidate biomarkers for discriminating the different outcomes of ACLF were selected. A prognostic model was constructed by a panel of four metabolites including phosphatidylinositol [20:4(5Z,8Z,11Z,14Z)/13:0], phosphatidyl ethanolamine (12:0/22:0), L-metanephrine and ethylbenzene, which could predict the worse prognosis in ACLF patients with sensitivity (84.4%) and specificity (89.5%) (area under the receiver operating characteristic curve [AUC] = 0.859, 95% confidence interval [CI] = 0.787-0.931). Compared with Model for End-Stage Liver Disease (MELD) score (AUC = 0.639, 95% CI = 0.526-0.753) and MELD-sodium (MELD-Na) score (AUC = 0.692, 95% CI = 0.582-0.803), EBC-associated metabolite signature model could better predict worse outcomes in patients with ACLF (p < 0.05). Using the MELD-Na score and EBC metabolite signatures, a decision tree model was built for predicting the prognosis of ACLF identified on logistic regression analyses (AUC = 0.906, 95% CI = 0.846-0.965). CONCLUSION: EBC metabolic signatures show promise as potential biomarkers for predicting worse prognosis of ACLF.

A prediction model for outcome in patients with HBV-ACLF based on predisposition, injury, response and organ failure.

We aimed to develop a prediction model based on the PIRO concept (Predisposition, Injury, Response and Organ failure) for patients with Hepatitis B Virus (HBV) related acute-on-chronic liver failure (ACLF). 774 patients with HBV related ACLF defined in the CANONIC study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification and regression tree was used to stratify patients into different nodes. The prediction model was then validated using an independent cohort (n = 155). Factors significantly associated with 90-day mortality were: P: age, gender and ACLF type; I: drug, infection, surgery, and variceal bleeding; R: systemic inflammatory response syndrome (SIRS), spontaneous bacteria peritonitis (SBP), and pneumonia; and O: the CLIF consortium organ failure score (CLIF-C OFs). The areas under the receiver operating characteristics curve (95% confidence interval) for the combined PIRO model for 90-day mortality were 0.77 (0.73-0.80). Based on the scores for each of the PIRO components and the cut-offs estimated from the classification and regression tree, patients were stratified into different nodes with different estimated death probability. Based on the PIRO concept, a new prediction model was developed for patients with HBV related ACLF, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed model will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes.

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.

Comparison of extracorporeal cellular therapy (ELAD®) vs standard of care in a randomized controlled clinical trial in treating Chinese subjects with acute-on-chronic liver failure.

BACKGROUND: Preliminary evidence of safety and efficacy of an extracorporeal cellular therapy (ELAD®) has been demonstrated in subjects with acute forms of liver failure. This study compared ELAD with standard of care in Chinese subjects with acute-on-chronic liver failure (ACLF), predominantly secondary to chronic viral hepatitis. SUBJECTS AND METHODS: Subjects meeting eligibility criteria were randomized to either the ELAD group or the control group. All subjects received plasma exchange and venovenous hemofiltration and either ELAD treatment for 3-5 days, unless terminated early, along with standard of care or standard of care alone (control) and were then followed up for 12 weeks. RESULTS: Forty-nine subjects (ELAD subjects, 32; controls, 17) were randomized under this protocol. Kaplan-Meier analysis of transplant-free survival (TFS) revealed a significant difference in favor of ELAD vs control (P=0.049, Wilcoxon signed-rank test). There was a significant difference in TFS on day 28 in ELAD vs control (P=0.022). In a multiple regression model, the relationship between group assignment and outcome was significant (P=0.031) when changes in food intake and Model for End-Stage Liver Disease (MELD) scores at screening were included as additional independent variables. The duration of ELAD treatment alone was a significant predictor of TFS (P=0.043). Median time to a 5-point increase in MELD, transplant, or death was longer than 72 days with ELAD vs 26 days for control (P=0.036). Total bilirubin level decreased by 25% during ELAD treatment vs 37% increase in the control group (P<0.001) over an equivalent period. Adverse events attributed to the ELAD system were expected and could be managed conservatively. Intergroup differences in certain vital signs and laboratory parameters were noted during treatment and generally resolved posttreatment. CONCLUSION: ELAD treatment was well tolerated by Chinese subjects with ACLF, predominately secondary to chronic viral hepatitis. Results demonstrate a significant improvement in TFS in ELAD vs control groups in association with significant improvements in serum bilirubin levels presumably related to improvement in hepatic function.

Prediction model of the progression of patients with acute deterioration of hepatitis B virus-related chronic liver disease to acute-on-chronic liver failure.

This study aimed to establish a new model for predicting acute-on-chronic liver failure (ACLF) (defined by the Chinese Medical Association), which potentially occurs among patients with acute deterioration (AD) of hepatitis B virus (HBV)-related chronic liver disease (CLD).A total of 754 patients with AD of HBV-related CLD (total bilirubin (TBIL) > 51.3 µmol/L and prothrombin activity (PTA) < 60%, 40% < PTA < 60% when TBIL ≥ 171.1 µmol/L) were retrospectively analyzed and divided into a training cohort (580 patients) and a validation cohort (174 patients). The ACLF occurrence probability of these patients was statistically analyzed within 4 weeks. In the training cohort, multivariate logistic regression analysis was performed to determine the independent predictors of ACLF occurrence and to develop a new prediction model. The validation cohort was utilized to verify and evaluate the value of the new prediction model.Within 4 weeks, 9.9% of the patients progressed to ACLF (12.0 ±â€Š6.7 days). The new prediction model was characterized by R = 3.090 + 0.035 × Age (years) - 0.050 × PTA (%) + 0.005 × TBIL (µmol/L) + 0.044 × D/T (%) - 0.072 × Na (mmol/L) + 0.180 × HBV DNA (log10IU/mL). The areas under the receiver operating characteristic curves of the training and validation cohorts in the new model were higher than those in the model for end-stage liver disease.The new prediction model could be used by clinicians to recognize patients with AD of HBV-related CLD with high risks of progressing to ACLF.

Clinical and virological implications of A1846T and C1913A/G mutations of hepatitis B virus genome in severe liver diseases.

OBJECTIVE: Mutations occurring within different genes of hepatitis B virus (HBV) genome may have different clinical implications. This study aimed to observe the clinical and virological implications of the A1846T and C1913A/G mutations of HBV genome in the development and treatment outcome of severe liver diseases, which has not been previously determined. MATERIALS AND METHODS: A total of 438 cases of patients with liver diseases were retrospectively reviewed, including 146 with mild chronic hepatitis B infection (CHB-M), 146 with severe chronic hepatitis B infection (CHB-S), and 146 with acute-on-chronic liver failure (ACLF). Partial or full-length HBV genome was directly sequenced. Replicons containing A1846T, C1913A or other mutant sequences, or the wild-type counterparts were constructed respectively, and then transfected into HepG2 cells for phenotype analysis. RESULTS: There was significant difference in the detection rates of A1846T (30.82%, 40.41% and 55.48%, respectively) and C1913A/G (15.52%, 28.77%, and 35.62%, respectively) among patients with CHB-M, those with CHB-S, and those with ACLF (p < .01). A1846T was significantly associated with the mortality of ACLF patients within six months after the disease onset (OR 1.704, p = .041). In vitro experiment revealed that A1846T mutant resulted in 3.20-fold and 1.85-fold increase of replication capacity and promoter activity, respectively compared with wild type counterpart (p < .001), while C1913A led to a significant decrease of core protein expression (p < .05). CONCLUSION: Occurrence of A1846T and C1913A is positively associated with clinical presentations of severe liver disease. A1846T mutation is significantly associated with poor prognosis of ACLF.