The Use of NACSELD and EASL-CLIF Classification Systems of ACLF in the Prediction of Prognosis in Hospitalized Patients With Cirrhosis.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium and the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) as an acute deterioration of cirrhosis with multiple organ failures and high short-term mortality. However, their diagnostic criteria differ. We aimed to compare these 2 criteria in the prediction of prognosis in hospitalized cirrhosis. METHODS: This was a prospective study of nonelectively hospitalized patients with cirrhosis (N = 468) from a single tertiary hospital between 2016 and 2018. Baseline characteristics, incidence, and types of organ failure and survival data at 7, 28, and 90 days were collected. Prognostic utilities of the 2 criteria were compared. RESULTS: One hundred thirty-seven of 468 patients (29.3%) had EASL-CLIF ACLF, and 35 of 468 (7.4%) had NACSELD ACLF. The 28-day transplant-free survival of ACLF was 58.4% using EASL-CLIF and 37.1% using the NACSELD criteria. In predicting 28-day mortality, the NACSELD criteria demonstrated significantly higher overall accuracy (92.0% vs 85.3%, P < 0.01), specificity (99.7% vs 84.0%, P < 0.001), and positive predictive value (97.1% vs 50.4%, P < 0.001) but lower sensitivity (49.3% vs 92.5%, P < 0.001) and negative predictive value (91.6% vs 98.5%, P < 0.001) than those of EASL-CLIF. The results were similar in predicting 7-day outcome. However, the overall accuracy became similar between NACSELD and EASL-CLIF ACLF criteria in predicting 90-day mortality (86.3% vs 88.7%, P = 0.27) because of the decrease of sensitivity and negative predictive value of NACSELD ACLF criteria. The prognostic performance of these 2 ACLF criteria was similar when applied to patients with or without hepatitis B virus infection as an etiology of cirrhosis. DISCUSSION: There are both caveats and utilities of NACSELD and EASL-CLIF ACLF criteria in prognosis prediction in patients with cirrhosis. NACSED criteria is highly accurate in predicting morality, whereas the EASL-CLIF criteria is more sensitive to identify patients who would benefit from liver transplantation.

The impact of HBV flare on the outcome of HBV-related decompensated cirrhosis patients with bacterial infection.

BACKGROUND: Hepatitis B virus (HBV) flare can occur in HBV patients either naïve or have interruption to treatment. Bacterial infection (BI) is a common complication of cirrhosis with potential severe outcomes. We aimed to assess the impact of HBV flare on the outcome of patients with HBV-related decompensated cirrhosis and BI. METHODS: This was a retrospective study from 2 tertiary academic hospitals in Shanghai, China of HBV patients admitted with or developed BI during admission. The characteristics of BI, prevalence of HBV flare, its impact on organ failure, acute-on-chronic liver failure (ACLF) and 90-day survival were evaluated. RESULTS: A total of 360 hospitalized patients (median age: 50 years, male: 79%, BI: at admission: 58.6%; during admission: 41.4%) were included. All patients including those with HBV flare (21%) received antiviral therapy after admission. Patients with HBV flare and BI had significantly higher percentage of liver (93.3% vs 48.8%), coagulation (64.0% vs 39.6%), cerebral (40.0% vs 21.8%) (all P < 0.01), and kidney failure (38.7% vs 26.3%, P < 0.05) compared to BI alone, associated with a higher risk of developing ACLF with a subdistribution hazard ratio (sHR) of 2.23 (95% confidence interval [CI]: 1.68-2.96). Multivariate analysis showed that ACLF development was the strongest risk factor for 90-day mortality (sHR, 95%CI: 7.36, 4.12-13.16). CONCLUSIONS: In HBV-related decompensated cirrhosis patients admitted with BI, HBV flare increased the risk of additional organ failures and ACLF, raising the risk of 90-day mortality by seven-fold. Optimization of HBV treatment in these patients should minimize the risk of HBV flare with improved outcomes.

Younger trend of cirrhosis incidence in genotype 3 HCV infected patients in Eastern China.

The diversity of HCV genotypes is ever-evolving and requires continuous surveillance. The aim of this study was to investigate the dynamics of HCV genotypes, and their associated demographic and clinical patterns in China. By searching computerized hospital information system, a total of 1155 HCV-positive patients eligible for analysis were retrospectively identified from 12 380 consecutive in-patients in the Department of Infectious Diseases, Ruijin Hospital in China between 2009 and 2014. The percentages of HCV genotype 1, 2, 3, or 6 were 61.3%, 12.8%, 18.5%, or 7.4%, respectively. The number of patients hospitalized for HCV infection increased gradually over the study period, particularly those infected by genotype 3 HCV. Patients of genotype 1, 2, 3, or 6 were significantly different. Genotype 1 or two patients were much older, with higher proportion of blood transfusion history. In contrast, genotype 3 or six patients were younger, predominantly male, with more exposure to intravenous drug use. The cirrhosis incidence was higher in genotype 1 or two patients, followed by genotype 3 and six patients. Strikingly, genotype 3 cirrhotic patients were younger, and their estimated infection durations were also shorter, suggestive of a faster disease progression in genotype 3 patients. Multivariate analysis demonstrated that presence of HBcAb was an independent predictor of cirrhosis (OR 2.19, 95%CI 1.27-3.42; P = 0.004). The leading increase and the younger trend of cirrhosis incidence in genotype 3 patients argue for a higher priority to manage the infection in this highly at-risk population.

Algorithm of Golgi protein 73 and liver stiffness accurately diagnoses significant fibrosis in chronic HBV infection.

BACKGROUND & AIMS: Serum Golgi protein 73 (GP73) is a potential biomarker for fibrosis assessment. We aimed to develop an algorithm based on GP73 and liver stiffness (LS) for further improvement of accuracy for significant fibrosis in patients with antiviral-naïve chronic hepatitis B virus (HBV) infection. METHODS: Diagnostic accuracy evaluation of GP73 and development of GP73-LS algorithm was performed in training cohort (n = 267) with an independent cohort (n = 133) for validation. RESULTS: A stepwise increasing pattern of serum GP73 was observed across fibrosis stages in patients with antiviral-naïve chronic HBV infection. Serum GP73 significantly correlated (rho = 0.48, P < .001) with fibrosis stage and was an independent predictor for the presence of significant fibrosis (OR, 95%CI: 1.02, 1.01-1.03, per increase in 1 ng/mL, P < .001). Both LS (AUROC, 95%CI: 0.82, 0.77-0.87, accuracy: 74.7%) and GP73 (AUROC, 95%CI: 0.76, 0.71-0.82, accuracy: 71.5%) well-predicted significant fibrosis and outperformed APRI (AUROC, 95%CI: 0.69, 0.63-0.76, accuracy: 66%) and FIB-4 (AUROC, 95%CI: 0.66, 0.60-0.73, accuracy: 63.6%). Using GP73-LS algorithm, GP73 < 63 in agreement with LS < 8.5 provided accuracy of 81.7% to excluded significant fibrosis. GP73 ≥ 63 in agreement with LS ≥ 8.5 provided accuracy of 93.3% to confirm significant fibrosis. Almost 64% or 68% of patients in the training or validation cohort could be accurately classified. CONCLUSIONS: Serum GP73 is a robust biomarker for significant fibrosis diagnosis. GP73-LS algorithm provided better diagnostic accuracy than currently available approaches. More than 60% antiviral naïve CHB patients could use this algorithm without resorting to liver biopsy.

Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is an acute deterioration of liver function on chronic liver disease with immune disorder. Th22 cells and IL-22 were correlated with inflammatory and autoimmune diseases. However, Th22 cells and IL-22 in the pathogenesis of HBV-ACLF remains to be elucidated. It was investigated the correlation between Th22 and prognosis in HBV-ACLF. METHODS: Seventy-one HBV-ACLF and 65 chronic hepatitis B patients were recruited. The peripheral frequencies of Th22, Th17 and Th1, or IL-22 and IL-17 were determined, using flow cytometry or ELISA, respectively. It was further analyzed the correlation between Th22 mediated circulating IL-22 and survival rate of HBV-ACLF patients. RESULTS: It was upregulated that the peripheral frequencies of Th22/Th17 cells as well as plasma IL-22 and IL-17 in HBV-ACLF patients, but the frequency of Th1 cells was decreased, compared with health controls. Elevated Th22 cells and IL-22 were correlated with HBV-ACLF disease severity. Elevated plasma IL-22 level (>29.5 pg/ml) was correlated with poor survival rate of HBV-ACLF patients at baseline, using Kaplan-Meier analysis. CONCLUSIONS: Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-ACLF. Th22 cells/IL-22 might be served as biomarkers for evaluating the prognosis of HBV-ACLF.

Protective effect of Th22 cells and intrahepatic IL-22 in drug induced hepatocellular injury.

BACKGROUND & AIMS: Th22 cells regulate host immunity against pathogenic invasion, including protecting host against chronic hepatitis B; however, the relationship between drug induced liver injury (DILI) and Th22/Th17 cells is still unclear. We investigated the role of Th22 cells in DILI development. METHODS: The frequencies of peripheral Th22/Th17/Th1 cells and intrahepatic IL-22/IL-17 production from DILI, non-DILI liver diseases, and healthy controls were examined. Plasma IL-22/IL-17 and the related cytokines were determined in DILI patients at week 0 (defined as the occurrence of liver injury within 7days), 4 and 24. Multivariable stepwise logistic regression was applied to explore the associations between various factors and recovery of DILI. RESULTS: The frequencies of Th22/Th17 cells were significantly higher in DILI onset patients than HC. Significant increase of Th22 cells and the related cytokines levels was observed in DILI with hepatocellular injury type. There was a positive correlation between intrahepatic IL-22 level and liver regeneration. Plasma IL-22 level was higher in DILI patients with improved liver function than unimproved function. Multivariable analysis showed that the odds ratio (OR) of plasma IL-22 at 4weeks was 1.054 [95% confidence interval (CI), 1.012, 1.124]. CONCLUSIONS: Increased peripheral and intrahepatic IL-22-secreting cells are detected in DILI. Th22 and its related cytokines might be hepato-protective, which might provide new perspective for understanding the immunopathogenesis of DILI. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.

Association of IL28B polymorphisms with peginterferon treatment response in Chinese Han patients with HBeAg-positive chronic hepatitis B.

AIMS: To investigate whether IL28B polymorphisms could affect the treatment response to peginterferon alpha (PEG-IFN) in chronic hepatitis B (CHB) patients in the Chinese Han population. METHODS: A total of 212 hepatitis B e antigen (HBeAg)-positive patients treated with PEG-IFN monotherapy were enrolled in this study. Genotype analysis was performed for IL28B rs12980275, rs12979860 and rs8099917 using the MassArray system. Response was defined as cases showing normal aminotransferase (ALT) levels, HBV DNA level < 200 IU/ml and HBeAg seroconversion after 48 weeks of PEG-IFN therapy. RESULTS: The patients were infected with hepatitis B virus (HBV) genotype B (44.8%) and C (55.2%) with a total response rate of 34.9%. For the three SNPs, there were significant differences between the response (R) and non-response (NR) groups both in allele frequencies and genotype distributions. IL28B genotype was independently associated with R for AA vs. N-AA (OR 2.70, 95% CL 1.21-6.01; P = 0.015) at rs12980275 after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC vs. N-CC (OR 2.56, 95% CL 1.15-5.67; P = 0.021) and rs8099917 TT vs. N-TT (OR 2.80, 95% CL 1.23-6.39; P = 0.015) respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R (OR 2.53, 95% CL 1.20-5.34; P = 0.015). CONCLUSIONS: Our study suggested that genetic variations in IL28B may play a critical role in PEG-IFN efficacy in HBeAg-positive CHB patients in Han Chinese.

[Clinical profiles of circulating plasmacytoid dendritic cells in chronic hepatitis B patients in response to pegylated-interferon alfa-2a treatment].

OBJECTIVE: To investigate the changes in circulating plasmacytoid dendritic cells (pDCs) in patients with chronic hepatitis B (CHB) during the course of treatment with pegylated-interferon alfa-2s (peg-IFNa-2a) and to determine the correlations with therapeutic response. METHODS: Forty-one patients with CHB who were receiving peg-IFNa-2a antiviral treatment for 48 weeks were enrolled in the study.Expression of the Toll-like receptor 9 (TLR9) on and frequency and functionality of the pDCs were analyzed at treatment weeks 0, 2, 12, 24, 36 and 48. RESULTS: All patients exhibited an initially rapid decrease in the numbers of circulating pDCs and showed CpG-induced endogenous IFNa production within the first 2 weeks of treatment.Subsequently, all responders displayed a continuous increase in pDC numbers as well as functionality, both of which peaked around week 12 of treatment; in addition, these treatment responses were accompanied by significantly increased levels of type 1 T helper cytokines (P less than 0.05), which did not occur in the non-responders. CONCLUSION: pDCs are involved in the initial therapeutic immune response stimulated by peg-IFNa-2a treatment.Recovery of blood pDC number and functionality may represent a predictor of favorable response to peg-IFNa-2a antiviral treatment in patients with CHB.

[Effects of oral antiviral agents on long-term outcomes of treatment-naive patients with HBV-related decompensated cirrhosis: a retrospective cohort study].

OBJECTIVE: To evaluate the efficacy of nucleos(t)ide analogues (NA) treatment and to assess the long-term outcomes, including survival, liver function improvement and virologic response, in patients with decompensated cirrhosis due to hepatitis B virus (HBV) infection. METHODS: Patients with Child-Turcotte-Pugh (CTP) scores more than or equal to 7, who had been treated with either lamivudine or other agents, but who were free of co-infection with other hepatitis virus were enrolled between January 2005 and December 2009. The study participants were subgrouped according to the antiviral drugs received or model for endstage liver disease (MELD) score for comparative analyses.Additionally, the 19 patients who were treated with NA for more than 5 years were investigated for changes in biochemical and virological indices, before and after the antiviral treatment. RESULTS: A total of 166 patients (125 males; 89 e-negative) and 52 untreated healthy patients (as control) were analyzed.The cohort of patients receiving antiviral therapy had significantly better 5-year actuarial survival than the untreated patients (74.1% vs.34.9%, P less than 0.001). For patients with MELD score more than or equal to 18, actuarial survival was not significantly different between the two groups (P=0.073). CONCLUSION: Antiviral therapy significantly increases survival and improves the clinical long-term outcome of patients with HBV-induced decompensated cirrhosis.Antiviral treatment should be initiated at an early stage to maximize benefit in the improvement of clinical status.

The safety concerns regarding immune checkpoint inhibitors in liver cancer patients rising mainly from CHB.

Aim: To analyze the safety of immune checkpoint inhibitors in primary liver cancer patients and to identify the risk factors for immune-related adverse events (irAEs). Methods: The study enrolled 106 patients with primary liver cancer, including 81 with hepatocellular carcinoma and 25 with intrahepatic cholangiocarcinoma. We analyzed the differences between groups in irAE occurrence, including those with and without targeted drugs and those who received interventional therapy. Results: The incidence of irAEs was 39%, with thyroid function, liver function, and skin events being the most common. There was no correlation among irAE incidence and the liver cancer type, stage, or severity; grade of Child-Pugh score; and Barcelona Clinical Liver Cancer classification. However, being overweight was a significant risk factor for irAEs, correlating with high body mass index. The combination of targeted drugs and/or transcatheter arterial chemoembolization therapy did not increase the incidence of irAEs. Conclusion: Being overweight is a potential risk factor for irAEs in primary liver cancer patients. However, there is no correlation between irAE incidence and the liver cancer type, stage, or severity or a combination of targeted drugs or transarterial chemoembolization therapy.

The 20 years transition of clinical characteristics and metabolic risk factors in primary liver cancer patients from China.

Background: The clinical characteristics of primary liver cancer (PLC) patients are changing, maybe due to hepatitis viral vaccination and lifestyle changes, etc. The linkage between these changes and outcomes among these PLCs has not yet been fully elucidated. Methods: It was identified total of 1691 PLC cases diagnosed between 2000 ~ 2020. Cox proportional hazards models were utilized to determine the connections between the clinical presentations and their close risk factor(s) from PLC patients. Results: The average age of PLC patients increased gradually from 52.74 ± 0.5 years in 2000 ~ 2004 to 58.63 ± 0.44 years in 2017 ~ 2020, accompanied by an increased proportion of females from 11.11% to 22.46%, and non-viral hepatitis-related PLC was raised from 1.5% to 22.35%. 840 (49.67%) PLC patients with alpha-fetoprotein (AFP) < 20ng/mL (AFP-negative). The mortality was 285 (16.85%) or 532 (31.46%) PLC patients with alanine transaminase (ALT) between 40 ~ 60 IU/L or ALT > 60 IU/L. The PLC patients with pre-diabetes/diabetes or dyslipidemia also increased from 4.29% or 11.1% in 2000 ~ 2004 to 22.34% or 46.83% in 2017 ~ 2020. The survival period of the PLC patients with normoglycemia or normolipidemic was 2.18 or 3.14 folds longer than those patients with pre-diabetes/diabetes or hyperlipidemia (P<0.05). Conclusions: It was gradually increased that age, the proportion of females, non-viral hepatitis-related causes, AFP-negative, and abnormal glucose/lipids among PLC patients. Proper control of glucose/lipids or ALT may improve the prognosis of PLCs.

miR-15b and miR-16 regulate TNF mediated hepatocyte apoptosis via BCL2 in acute liver failure.

Acute liver failure (ALF) still has an unacceptable high mortality rate, despite substantial improvements with multidisciplinary care. The precise underlying mechanism of ALF remains to be explored. It has been reported that microRNAs (miRNAs) are novel regulators in a number of liver diseases, but the role of miRNAs in the development of ALF is not fully understood. An ALF murine model was generated by ip injection of D: -GalN/LPS, which was confirmed with histopathology and biochemistry. The hepatic miRNA expression profile in ALF was determined by microarray and verified by qRT-PCR. The functions and signal pathways of the targeted genes of these deregulated miRNAs were predicted, using bioinformatics analysis. The possible underlying mechanism was investigated by exploring the relationship between miRNA modification and hepatocyte apoptosis. There were a total of 95 significantly changed miRNAs in ALF compared to mock-treated (P < 0.01). Among these 95 miRNAs, 20 were up-regulated and 26 were down-regulated at both 5 and 7 h time points. Bioinformatics analysis predicted that some of these 46 miRNAs were involved in apoptosis. Among the up-regulated miRNAs involved in apoptosis, miR-15b and miR-16 showed the highest enrichment and targeted the common anti-apoptotic gene, BCL2. Our in vitro data demonstrated that miR-15b and/or miR-16 regulated BCL2 at the protein level. Inhibition of miR-15b and/or miR-16 reduced hepatic apoptosis and TNF production. These data suggest that miR-15b and miR-16 regulate TNF mediated hepatic apoptosis via BCL2 during ALF, and may shed light on the development of a therapeutic strategy for treatment of ALF.

[Clinical and pathological features in 138 cases of drug-induced liver injury].

OBJECTIVE: To explore the categories of drugs causing hepatotoxicity and analyze the clinical and histological features of the corresponding drug-induced liver injury (DILI), in order to gain insights into potential diagnostic factors for DILI. METHODS: A total of 138 DILI patients treated at our hospital from April 2008 to April 2010 were retrospectively analyzed. The responsible drug for each DILI case was recorded. The Roussel Uclaf Causality Assessment Method (RUCAM) had been used to diagnose DILI. Only cases that had scored as highly probable or probable (more than or equal to 6 points by RUCAM) were included in this study. The patients' general condition, clinical manifestations, and serum biochemical and immunological parameters were assessed. Sixty-six of the patients underwent liver biopsy, and were assessed for liver pathological changes. Clinical and laboratory test data were collected and used to classify the total 138 cases as hepatocellular injury, cholestatic, or mixed hepatocellular-cholestatic types. RESULTS: Within our patient population, the leading cause of DILI was Chinese herb medicine, accounting for 53.62% of cases. Antibiotics were implicated in 7.97% of cases, and dietary supplement in 6.52% of cases. Correlation between the clinical features and histological injury pattern was stronger at the time of biopsy (more than or equal to 3 days after laboratory results) (kappa = 0.63, P less than 0.05) than at the onset of DILI (kappa = 0.25, P less than 0.05). All modified hepatic activity index (HAI) necroinflammatory scores and fibrosis scores were more severe in the cholestatic and mixed injury types than in the hepatocellular injury type (P less than 0.01 and P less than 0.05, respectively). CONCLUSION: Chinese herbal medicine, dietary supplements and antibiotics were the main causes of DILI in our patient population. The clinical and histological features correlated well, especially at later stages of DILI. The degree of inflammation and fibrosis was significantly higher in cholestatic and mixed hepatocellular-cholestatic injury types than in the hepatocellular injury type. Assessment of both clinical and pathological features may represent a more accurate diagnostic method for DILI.

A novel model based on qAnti-HBc and conventional biomarkers for identifying significant liver injury among CHB patients with ALT ≤ ULN.

BACKGROUND: Antiviral therapy is not routinely recommended for CHB patients with ALT ≤ ULN (CHB-NALT), based on current international guidelines. However, it is debatable if antiviral treatment should be offered for CHB-NALT patients, because significant liver injury is observed from liver biopsy of some CHB-NALT patients. Quantification of anti-HBc (qAnti-HBc) can predict antiviral response in CHB patients, while its role in CHB-NALT patients remains to be explored. AIM: To determine if it is reliable that the novel non-invasive model based mainly on qAnti-HBc and other conventional biomarkers for providing objective value among CHB-NALT patients with antiviral therapy, in direct comparison with liver biopsy. METHODS: 542 or 110 liver biopsied CHB-NALT patients from 2015 to 2020 or in 2021 were included in training set or validation set. Circulating IL-1ß, IL-2, IL-4, IL-12p70, IL-17, TNF and IFNα were determined in the training set. A non-invasive model was developed based on qAnti-HBc and other conventional biomarkers. RESULTS: Among 423/542 (78%) patients with significant liver injury in the training set, 47% were in grey-zone. Circulating IL-1ß, IL-12p70, IL-17 in the CHB-NALT patients with liver injury was significantly higher than these without liver injury in the training set (p < 0.01). No significant difference of IL-1ß, IL-12p70, IL-17 was observed between CHB-NALT patients with significant liver injury and active CHB with elevated ALT in the training set. There was inverse correlation between liver injury grades and IFNα, IL-4, or IL-2 in these patients (p < 0.05). Serum qAnti-HBc level was significantly higher with CHB-NALT patients with liver injury than these without in the training set (P < 0.01). ALT/ULN, AST, PLT and qAnti-HBc were identified as independent predictors for significant liver injury. Furthermore, our current model demonstrated a good performance in predicting significant liver injury, i.e. AUROCs of 0.95 or 0.86 in training set or validation set. The model cut-off value for anti-viral therapy at ≥1.471. CONCLUSIONS: qAnti-HBc appears to be well correlated with the hepatic damage, in direct comparison with liver biopsy from CHB-NALT patients. The novel model developed seems to be reliable for predicting liver injury in CHB-NALT patients. Such model also provides objective value for decision making of antiviral therapy.

Genetic Variations of ALDH (rs671) Are Associated With the Persistence of HBV Infection Among the Chinese Han Population.

Alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), members of the alcohol dehydrogenase family, have important roles in liver diseases. The roles of the polymorphisms of ADH1B rs1229984 and ALDH2 rs671 in hepatitis B virus (HBV) susceptibility and persistent infection were investigated in the present study. Total 1,034 patients with hepatitis B [99 acute hepatitis B (AHB), 521 chronic hepatitis B (CHB), 158 acute-on-chronic liver failure (ACLF), 159 liver cirrhosis (LC), and 97 hepatocellular carcinoma (HCC)] and 1,262 healthy controls (HCs) of the Chinese Han population were recruited, and single nucleotide polymorphisms (SNPs) of rs671 and rs1229984 were genotyped. Independent and joint roles of rs671 and rs1229984 in HBV infection were analyzed. The results showed that rs671 genotypes had a significantly different distribution among different subgroups. Compared with HCs, the frequency of rs671-AA genotype was higher in hepatitis B individuals, especially in the CHB group [adjusted OR (95%CI) = 1.899 (1.232-2.928), p = 0.003, in the co-dominant model], which showed a significant positive association. It was further confirmed that CHB individuals who carried ALDH2 rs671-AA genotype had a higher risk of persistent HBV infection and higher HBV-DNA quantitation compared with those with GG/GA genotype. In addition, the rs671-AA genotype might predict HCC incidence in patients with CHB. There were no different distributions of alleles or genotypes in rs671 mutant among AHB, ACLF, LC, or HCC groups compared with HCs. These data suggested the possible hazardous role of rs671-AA variant in HBV infection and persistence.

External Validation of aMAP Hepatocellular Carcinoma Risk Score in Patients With Chronic Hepatitis B-Related Cirrhosis Receiving ETV or TDF Therapy.

Background and Aim: A prediction model of hepatocellular carcinoma (HCC) risk in patients with chronic liver diseases, based on age, male sex, albumin-bilirubin, and platelets (aMAP), has been previously reported. We validated the aMAP score and compared its performance to those of other risk scores in an independent at-risk cohort. Methods: Treatment-naïve patients with chronic hepatitis B-related compensated cirrhosis who received entecavir or tenofovir monotherapy for at least 12 months were enrolled in this study. The performances of the aMAP and other HCC risk scores were assessed using Harrell's c-index, and predefined cut-off values were evaluated using survival analysis. Results: Of the 1,042 patients, 131 (12.6%) developed HCC during a median follow-up of 41 months. The aMAP score provided the highest Harrell's c-index (0.724), followed by CAMD (0.719), mPAGE-B (0.719), and PAGE-B (0.695). The 5-year cumulative HCC probabilities were 2.9% for patients with a low aMAP score (<50), 11.2% for patients with an intermediate aMAP score (50-60), and 27.9% for patients with a high aMAP score (>60). Using both aMAP and mPAGE-B, 11.6% of patients were identified as low risk with a negative predictive value of 98.2% for not developing HCC within 5 years. Patients with aMAP >60 and diabetes exhibited an extremely high risk of HCC, with a cumulative incidence of 49.3% at 5 years. The predictive performance of aMAP with a reassessment at 1 year after the initiation of antiviral therapy outperformed the predictive performance of aMAP at enrollment. Conclusions: The aMAP score accurately predicted the risk of HCC in at-risk patients with compensated cirrhosis undergoing antiviral therapy. A combination of the aMAP score and diabetes status could further stratify the risk of HCC.

Application of Fatty Liver Inhibition of Progression Algorithm and Steatosis, Activity, and Fibrosis Score to Assess the Impact of Non-Alcoholic Fatty Liver on Untreated Chronic Hepatitis B Patients.

BACKGROUNDS AND PURPOSE: Concurrent non-alcoholic fatty liver disease (NAFLD) in chronic hepatitis B (CHB) patients is a frequent and increasingly concerning problem because of the NAFLD pandemic. Admittedly, NAFLD can progress to non-alcoholic steatohepatitis (NASH) and severe fibrosis. Direct evidence of the fibrotic effect of NAFLD or NASH in chronic hepatitis B virus (HBV) infection remains lacking. We aimed to reveal the influence of concurrent histologically proven fatty liver diseases in fibrogenesis with chronic HBV infection. METHODS: We performed a retrospective cross-sectional study on a liver biopsy population of CHB patients without excessive alcohol intake to evaluate the prevalence of concurrent histologically proven NAFLD or NASH according to the fatty liver inhibition of progression (FLIP) algorithm and its association with the liver fibrosis stage. RESULTS: Among 1,081 CHB patients, concurrent NAFLD was found in 404 patients (37.4%), among whom 24.0% (97/404) have NASH. The presence of NASH was an independent predictor of significant fibrosis (odds ratio (OR), 2.53; 95% CI, 1.52-4.21; p < 0.001) and severe fibrosis (OR, 1.83; 95% CI, 1.09-3.09; p = 0.023) in all patients, as well as in patients with normal alanine aminotransferase (ALT) (predicting significant fibrosis, OR, 2.86, 95% CI, 1.34-6.10; p = 0.007). The presence of lobular inflammation (p < 0.001) or presence of cytological ballooning (p < 0.001), rather than presence of steatosis (p = 0.419), was related with severity of fibrosis in Spearman's correlation analysis. CONCLUSIONS: Concurrent NAFLD is common in CHB patients, and NASH is an independent risk factor potentiating significant fibrosis by 2.53-fold and severe fibrosis by 1.83-fold. While coping with chronic HBV infection, routine assessment of co-existing NAFLD or NASH is also important.

Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase.

BACKGROUND & AIMS: Normal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. METHODS: CHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). RESULTS: There was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg- patients. HBsAg at baseline and week 24 were strong predictors of "low HBsAg at week 48". CONCLUSION: Long term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg- patients with baseline HBsAg<2.66 log IU/ml to achieve "low HBsAg at week 48".

Bacterial infection triggers and complicates acute-on-chronic liver failure in patients with hepatitis B virus-decompensated cirrhosis: A retrospective cohort study.

BACKGROUND: Reports on bacterial infection (BI) in decompensated cirrhosis (DC) is mainly from alcoholic cirrhosis. The role of BI as a trigger or complication of acute-on-chronic liver failure (ACLF) in patients with hepatitis B virus decompensated cirrhosis (HBV-DC) remains to be investigated. AIM: To investigate the impact of BI on the outcomes of the patients with HBV-DC admitted into the hospital with or without ACLF. METHODS: This retrospective study included patients with HBV-DC admitted to two tertiary centers in China. In-hospital overall survival, 90-d transplant-free survival, 5-year post-discharge survival, and cumulative incidence of ACLF were evaluated. Risk factors for death were analyzed considering liver transplantation as a competing event. RESULTS: A total of 1281 hospitalized HBV-DC patients were included; 284 had ACLF at admission. The overall prevalence of BI was 28.1%. The patients with BI had a significantly lower in-hospital survival and transplant-free 90-d survival than those without, in both the patients admitted with and without ACLF. The presence of BI significantly increased the risk of developing ACLF [sub-distribution hazard ratio (sHR) = 2.52, 95%CI: 1.75-3.61, P < 0.001] in the patients without ACLF. In the patients discharged alive, those who had an episode of BI had a significantly lower 5-year transplant-free survival. BI was an independent risk factor for death in the patients admitted without ACLF (sHR = 3.28, 95%CI: 1.93-5.57), while in ACLF admissions, the presence of pneumonia, but not other type of BI, independently increased the risk of death (sHR = 1.87, 95%CI: 1.24-2.82). CONCLUSION: BI triggers ACLF in patients with HBV-DC and significantly impairs short-term survival. HBV-DC patients should be monitored carefully for the development of BI, especially pneumonia, to avoid an adverse outcome.

Expression of angiotensin-converting enzyme 2 in CCL4-induced rat liver fibrosis.

The renin angiotensin system (RAS) plays a major role in liver fibrosis. A novel homologue of angiotensin converting enzyme, ACE2, was identified as a negative regulator of RAS as it degrades Ang II to Ang1-7. We investigated in vivo the expression of ACE2 in liver fibrosis. We evaluated the relationship between biochemical variables and liver tissue expression of ACE2, the correlation between a histological assessment of liver fibrosis and liver tissue expression of ACE2. Male SD rats were randomly divided into a CCL4 group which received injections of CCL4 and the control group which received injections of olive oil. Liver pathology was examined by H&E and Sirius red staining, and real-time PCR was performed to determine the gene expression levels of ACE2 and ACE. Real-time PCR analysis revealed that ACE2 mRNA was higher at the two-, four-, and six-week time points, respectively (p<0.01). Similarly, hepatic ACE mRNA was significantly increased after CCL4 injection. There was a significant correlation between ACE and ACE2 gene expression (r=0.750, P<0.001). ACE2 gene expression strongly correlated with ALT (r=0.669, P<0.0001) and AST levels (r=0.815, P<0.0001). There was a significant correlation between circulating ACE2 and histological scores of liver fibrosis. ACE2 and ACE gene expression correlated with the ISHAK score (r=0.850, P<0.001; r=0.806, P<0.001). There was a significant relationship between ACE2 gene expression and the degree of liver fibrosis. ACE2 plays a crucial role in liver fibrogenesis.