Value of combined baseline serum HBV markers in predicting HBeAg seroconversion in chronic hepatitis B patients treated by nucleos(t)ide analogues / 临床肝胆病杂志

Objective To investigate the ability of combined baseline serum markers, i.e., HBV DNA, HBV RNA, HBsAg, and HBcrAg, to predict HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) treated by nucleos(t)ide analogues. Methods A retrospective analysis was performed for 83 HBeAg-positive patients selected as subjects from the prospective CHB follow-up cohort established by Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, from June 2007 to July 2008, and the baseline serum levels of HBV DNA, HBV RNA, HBsAg, and HBcrAg were analyzed. The t -test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Spearman method was used for correlation analysis. A Cox regression model was established to calculate HBeAg seroconversion prediction score, and the time-dependent receiver operating characteristic curve was used to evaluate the ability of combined markers in predicting HBeAg seroconversion. The Kaplan-Meier method was used to calculate cumulative seroconversion rate in each group, and the Log-rank test was used for comparison between groups. Results For the 83 HBeAg-positive patients, the median follow-up time was 108 months, and 44.58%(37/83) of these patients achieved HBeAg seroconversion. Compared with the non-seroconversion group, the HBeAg seroconversion group had significantly lower baseline serum levels of HBV DNA [6.23(1.99-9.28) log 10 IU/mL vs 7.69(2.05-8.96) log 10 IU/mL, Z =-2.345, P =0.019] and HBV RNA [4.81(1.40-7.53) log 10 copies/mL vs 6.22(2.00-8.49) log 10 copies/mL, Z =-1.702, P =0.010], and there were no significant differences in the levels of HBsAg and HBcrAg between the two groups ( P > 0.05). The Cox regression equation constructed based on the above serum markers showed a median score of 0.95(range 0.37-3.45) for predicting HBeAg seroconversion. In the total population, the combined score was negatively correlated with HBsAg, HBV DNA, HBV RNA, and HBcrAg ( r =-0.697, -0.787, -0.990, and -0.819, all P < 0.001). Based on the median prediction score, the patients were divided into high HBeAg seroconversion group and low HBeAg seroconversion group; as for the prediction of HBeAg seroconversion rate at 36, 60, and 84 months, the high HBeAg seroconversion group had a seroconversion rate of 43.90%, 51.20%, and 63.10%, respectively, while the low HBeAg seroconversion group had a seroconversion rate of 9.60%, 17.00%, and 19.8%, respectively, and there was a significant difference between the two groups ( χ 2 =11.6, P < 0.001). Conclusion The combined prediction score based on baseline serum HBV markers can predict HBeAg seroconversion in CHB patients treated by nucleos(t)ide analogues.

Serum Anti-Fumarate Hydratase Autoantibody as a Biomarker for Predicting Prognosis of Acute-on-Chronic Liver Failure

Background/Aims@#To investigate the autoantibody against fumarate hydratase (FH), which is a specific liver failure-associated antigen (LFAA) and determine whether it can be used as a biomarker to evaluate the prognosis of acute-on-chronic liver failure (ACLF). @*Methods@#An immunoproteomic approach was applied to screen specific LFAAs related to differential prognosis of ACLF (n=60). Enzyme-linked immunosorbent assay (ELISA) technology was employed for the validation of the frequency and titer of autoantibodies against FH in ACLF patients with different prognoses (n=82). Moreover, we clarified the expression of autoantibodies against FH in patients with chronic hepatitis B (n=60) and hepatitis B virus-related liver cirrhosis (n=60). The dynamic changes in the titers of autoantibodies against FH were analyzed by sample collection at multiple time points during the clinical course of eight ACLF patients with different prognoses. @*Results@#Ultimately, 15 LFAAs were screened and identified by the immunoproteomic approach.Based on ELISA-based verification, anti-FH/Fumarate hydratase protein autoantibody was chosen to verify its expression in ACLF patients. ACLF patients had a much higher anti-FH autoantibody frequency (76.8%) than patients with liver cirrhosis (10%, p=0.000), patients with chronic hepatitis B (6.7%, p=0.022), and normal humans (0%, p=0.000). More importantly, the frequency and titer of anti-FH protein autoantibodies in the serum of ACLF patients with a good prognosis were much higher than that of patients with a poor prognosis (83.9% vs 61.5%, p=0.019; 1.41±0.85 vs 0.94±0.56, p=0.017, respectively). The titer of anti-FH autoantibodies showed dynamic changes in the clinical course of ACLF. @*Conclusions@#The anti-FH autoantibody in serum may be a potential biomarker for predicting the prognosis of ACLF.

UGT1A1 gene polymorphisms in patients with Gilbert syndrome and Crigler-Najjar syndrome type Ⅱ / 临床肝胆病杂志

Objective To investigate the differences in UGT1A1 gene mutation sites, haplotypes, and diplotypes between patients with Gilbert syndrome (GS) and those with Crigler-Najjar syndrome type Ⅱ (CN-2). Methods A retrospective analysis was performed for the clinical data of 138 patients with GS or CN-2 who attended Beijing YouAn Hospital, Capital Medical University, from January 1, 2010 to December 31, 2019, with 109 patients in the GS group and 29 patients in the CN-2 group, and the differences in mutation sites were analyzed between the two phenotypes. The Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analyses of mutation sites. Strong LD was defined as both | D ′| and r 2 > 0.8, and moderate LD was defined as | D ′| > 0.8 and r 2 > 0.4. Results UGT1A1 gene detection was performed for all patients, and mutations mainly included -3279T > G mutation (104 patients, 75.36%) and -3152G > A mutation (82 patients, 59.42%) in the upstream promoter PBREM region, a promoter TATA box TA insertion mutation (88 patients, 63.77%), and c.211G > A mutation in Exon 1 of the coding region (66 patients, 47.83%). Compared with the CN-2 group, the GS group had a significantly higher proportion of PBREM region -3279T > G mutation (82.57% vs 48.28%, χ 2 =14.508, P A mutation (68.81% vs 24.14%, χ 2 =18.955, P (TA) 7 mutation (72.48% vs 31.03%, χ 2 =17.027, P 0.8, r 2 > 0.8) between (TA) 6 > (TA) 7 and -3152G > A and moderate LD (| D ′| > 0.8, r 2 > 0.4) between (TA) 6 > (TA) 7 and -3279T > G, between -3152G > A and -3279T > G, between (TA) 6 > (TA) 7 and c.211G > A, and between -3279T > G and c.211G > A. Haplotype frequency analysis showed that compared with the CN-2 group, the GS group had a significantly higher frequency of haplotype -3279G—-3152A—(TA) 7 (45.72% vs 17.24%, χ 2 =7.833, P =0.005) and significantly lower frequencies of c.1456G (4.10% vs 16.48%, χ 2 =4.873, P =0.027) and c.211A—c.1456G (1.86% vs 24.90%, χ 2 =15.210, P < 0.001). The diplotype analysis showed that diplotypes consisting of haplotype c.1456G or c.211A—c.1456G were associated with a higher level of total bilirubin (TBil). Conclusion There are differences in common mutation sites and major haplotypes of the UGT1A1 gene between patients with GS and those with CN-2, and the common diplotypes of CN-2 correspond to a higher level of TBil.

Comparison of two quantitative real-time PCR methods for serum HBV RNA in patients with HBeAg-positive chronic hepatitis B: A propensity score matching study / 临床肝胆病杂志

Objective To investigate the consistency between Shengxiang (S) and Xinbo (X) real-time PCR methods in the quantification of HBV RNA. Methods In the prospective follow-up cohort of 108 chronic hepatitis B (CHB) patients established from July 2007 to August 2008, 20 patients with HBeAg seroconversion were selected, and 20 patients without seroconversion were selected by propensity score matching at a ratio of 1∶ 1. The two quantification methods from S and X companies were used, and a retrospective analysis was performed for HBV RNA in serum samples at baseline and weeks 12, 24, and 48. The paired t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data. The Pearson correlation coefficient, intraclass correlation coefficient (ICC), and the Bland-Altman method were used to evaluate the consistency of the two quantification methods. Results A total of 132 serum samples were tested by S reagent, and 154 were tested by X reagent; the detection rate of HBV RNA was 100% by both reagents. A total of 131 serum samples were tested by both reagents, with 34 samples at baseline and 29, 35, and 33 samples, respectively, at weeks 12, 24, and 48 of follow-up; at these four time points, the HBV RNA quantification data detected by X reagent were significantly higher than those detected by S reagent (5.75±1.64/5.43±1.73/5.13±1.54/4.76±1.55 log 10 copies/mL vs 4.80±1.48/4.52±1.53/4.10±1.50/3.92± 1.43 log 10 copies/mL, t =8.348, t =5.341, Z =-5.086, Z =-4.762, all P < 0.001). The correlation analysis of the two methods showed a Pearson correlation coefficient of 0.915 (95% confidence interval [ CI ]: 0.836-0.957) and an ICC of 0.771(95% CI : -0.021 to 0.931) at baseline, a Pearson correlation coefficient of 0.849(95% CI : 0.701-0.927) and an ICC of 0.733(95% CI : 0.138-0.902) at week 12, a Pearson correlation coefficient of 0.951(95% CI : 0.905-0.975) and an ICC of 0.776(95% CI : -0.058 to 0.942) at week 24, and a Pearson correlation coefficient of 0.933(95% CI : 0.867-0.967) and an ICC of 0.804(95% CI : -0.014 to 0.944) at week 48 (all P < 0.05). The Bland-Altman analysis showed that the difference of 96.18%(126/131) samples tested by the two methods was within the mean difference±1.96 standard deviation. Conclusion HBV RNA quantification by X reagent is higher than that by S reagent, while the two real-time PCR quantification methods show a good consistency in CHB patients with HBeAg seroconversion and those without seroconversion.

Clinical and Immunological Factors Associated with Postpartum Hepatic Flares in Immune-Tolerant Pregnant Women with Hepatitis B Virus Infection Treated with Telbivudine

Background/Aims@#To investigate postpartum hepatic flares and associated factors in highly viremic pregnant patients in the immune tolerance phase who adopted telbivudine (LdT) treatment in the last trimester to reduce vertical transmission of hepatitis B virus. @*Methods@#Hepatitis B e antigen (HBeAg)-positive, highly viremic pregnant women were recruited for this prospective study. Treatment with LdT was started from 28 weeks of gestation. Virological and biochemical markers were examined before LdT treatment, antepartum and postpartum. Serial blood samples at the same time were collected to detect cytokines and cortisol (COR). @*Results@#Fifty-six of 153 patients (36.6%) had postpartum hepatic flares, defined as a 2-fold increase in alanine aminotransferase 6 weeks after delivery. Age and the antepartum alanine aminotransferase and postpartum HBeAg levels were independent influencing factors of postpartum hepatic flares. Cytokines showed no regularity during or after pregnancy. Compared with the patients with no postpartum flares, the patients with flares had lower baseline interferon γ and COR levels (p=0.022 and p=0.028) and higher postpartum interferon γ levels (p=0.026). @*Conclusions@#A high proportion of highly viremic and immune-tolerant pregnant patients treated with LdT in the last trimester had postpartum hepatic flares, which implied that these patients entered the immune clearance phase after delivery. Thus, this may create an appropriate opportunity for re-antiviral therapy.

Current status of the research on low-level viremia in chronic hepatitis B patients receiving nucleos(t)ide analogues / 临床肝胆病杂志

Nucleos(t)ide analogues (NAs), which are widely used as the first-line anti-hepatitis B virus (HBV) drugs in clinical practice, can effectively inhibit the replication of HBV DNA, significantly slow down disease progression in chronic hepatitis B (CHB) patients, and reduce the development of end-stage liver diseases such as liver failure and liver cancer. However, for some CHB patients receiving first-line NAs for 48 weeks or longer, serum HBV DNA is still persistently or intermittently higher than the lower detection of limit of sensitive nucleic acid detection reagents. After discussion by the authors, low-level viremia (LLV) is defined as follows: persistent LLV refers to the condition in which CHB patients, who receive entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate for ≥48 weeks, test positive for HBV DNA by two consecutive detections with sensitive quantitative PCR, with an interval of 3-6 months, but have an HBV DNA level of ＜2000 IU/ml; intermittent LLV refers to the condition in which patients test positive for HBV DNA intermittently by at least three consecutive detections with sensitive quantitative PCR, with an interval of 3-6 months, but have an HBV DNA level of ＜2000 IU/ml. For the diagnosis of LLV, the issues of poor compliance and drug-resistant mutations should be excluded. LLV might be associated with the increased risk of progression to liver fibrosis or hepatocellular carcinoma in patients with liver cirrhosis under NA treatment, but there are still controversies over whether the original treatment regimen with NAs should be changed after the onset of LLV. This article summarizes the incidence rate of LLV under NA treatment and the influence of LLV on prognosis and analyzes the possible mechanisms of the osnet of LLV, so as to provide a reference for the management of LLV in patients treated with NAs.

Value of common clinical indices and noninvasive liver fibrosis scores in the diagnosis of advanced liver fibrosis in hepatic-type Wilson’s disease in China / 临床肝胆病杂志

ObjectiveTo investigate the association of common clinical indices and noninvasive liver fibrosis scores with hepatic-type Wilson’s disease (WD) in Chinese patients and their ability to identify advanced liver fibrosis. MethodsA retrospective analysis was performed for the clinical data of 236 Chinese patients with WD who were diagnosed and treated in Beijing YouAn Hospital and China-Japan Friendship Hospital from May 1996 to April 2020. A total of 26 patients with hepatic-type WD who underwent liver pathological examination and had complete clinical data were enrolled; the METAVIR score was used to determine liver fibrosis stage, and the patients were divided into advanced liver fibrosis (F3 and F4 stages) group and non-advanced liver fibrosis (F0, F1, and F2 stages) groups. Three noninvasive liver fibrosis scores ［Sheth index, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) index］ were calculated for both groups, and the above indices and related clinical indices were compared between the two groups. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the Fisher’s exact test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used for further analysis of indices with statistical significance, and the clinical indices and scoring criteria correlated with liver fibrosis degree were screened out; the receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated. ResultsMost of the patients in this study developed the disease in childhood and adolescence, and among these patients, 10 (38.5%) had positive K-F ring and 17 (65%) were in the stage of advanced liver fibrosis. There were significant differences between the advanced liver fibrosis group and the non-advanced liver fibrosis group in white blood cell count (WBC) (Z=-2.102, P=0.036), hemoglobin (Hb) (t=-2.860, P=0009), platelet count (PLT) (t=-4.053, P＜0.001), direct bilirubin (DBil) (Z=-2.130, P=0.033), albumin (Alb) (t=-2.875, P=0.008), and Sheth index (Z=-3.369, P=0.001). WBC, Hb, PLT, and Alb were negatively correlated with liver fibrosis degree in WD patients (r=-0.587, -0.610, -0.656, and -0.411, all P＜0.05), and DBil and Sheth index were positively correlated with liver fibrosis degree (r=0.486 and 0.711, both P＜0.05). The ROC curve analysis showed that WBC, DBil, Sheth index, Hb, PLT, and Alb had an AUC of ＞0.7, among which Sheth index had the largest AUC of 0.908, with a sensitivity of 70.6%, a specificity of 100.0%, a positive predictive value of 100.0%, and a negative predictive value of 64.3%. ConclusionSheth index has a better diagnostic efficiency than the other clinical indices alone and can well identify advanced liver fibrosis in Chinese patients with hepatic-type WD.

Role of serum hepatitis B virus RNA quantification in guiding antiviral therapy for chronic hepatitis B / 临床肝胆病杂志

Chronic hepatitis B virus (HBV) infection and end-stage liver disease caused by such infection pose a serious threat to the health of Chinese citizens. The presence of HBV cccDNA is the main reason for the difficulties in the treatment of chronic hepatitis B and recurrence after drug withdrawal. HBV RNA, as a new serum marker, is produced by cccDNA transcription, and theoretically, it can reflect the level and transcriptional activity of cccDNA in hepatocytes. This article mainly introduces the formation of serum HBV RNA and analyzes its significance in evaluating the activity or status of cccDNA in liver tissue and predicting patients’ response during antiviral therapy and after drug withdrawal. Moreover, it is pointed out that further large-scale clinical studies are needed to verify and improve the clinical significance of serum HBV RNA measurement, so as to further optimize the regimens of antiviral therapy and guide the precision treatment of patients.

Clinical features and differential diagnosis of hemolytic jaundice / 临床肝胆病杂志

Hemolytic jaundice has various etiologies and clinical manifestations. Although some patients have hemolysis, they may have jaundice as the initial manifestation due to unobvious or mild anemia, and the disease may last for a long time with difficulties in treatment and can be misdiagnosed as unexplained chronic hepatitis and jaundice with unknown cause. In addition, it may be easily confused with congenital indirect bilirubinemia including Gilbert’s syndrome, which may lead to missed diagnosis and delays in diagnosis and treatment. Physicians in hepatology should master the knowledge of hemolytic jaundice and chronic hemolytic diseases. This article summarizes the clinical features of hemolytic jaundice and thoughts in differential diagnosis and briefly introduces the clinical features of common chronic hemolytic diseases, so as to provide a reference for clinical physicians.

Research advances in predictive markers for HBeAg seroconversion in chronic hepatitis B patients treated with nucleos(t)ide analogues / 临床肝胆病杂志

Nucleos(t)ide analogues (NAs) are effective inhibitors for HBV replication and have become the preferred antiviral regimen for most patients with chronic hepatitis B (CHB). HBeAg seroconversion is an important index used to evaluate the durability and efficacy of antiviral therapy in HBeAg-positive CHB patients. The search for biomarkers that can predict HBeAg clearance or seroconversion after NAs treatment plays an important role in the selection of antiviral drugs, the adjustment of treatment regimens, and the achievement of individualized treatment. This article reviews the value of related markers, including HBV DNA, HBV RNA, anti-HBc, and HBcrAg, in predicting HBeAg clearance or seroconversion in CHB patients treated with NAs.

Research advances in mutation characteristics of the UGT1A1 gene in Gilbert syndrome and its influence on intrahepatic and extrahepatic systems / 临床肝胆病杂志

Gilbert syndrome is the most common type of hereditary hyperbilirubinemia with a high incidence rate. This article briefly describes the research advances in epidemiological characteristics of Gilbert syndrome, common UGT1A1 gene mutation sites, and the influence of Gilbert syndrome on intrahepatic and extrahepatic diseases. It is pointed out that an understanding of these aspects plays an important role in the diagnosis and treatment of Gilbert syndrome and the prevention and treatment of intrahepatic and extrahepatic diseases.

Clinical features and diagnosis of four common types of congenital hyperbilirubinemia / 临床肝胆病杂志

Congenital hyperbilirubinemia is an inherited metabolic liver disease commonly seen in clinical practice, and various atypical manifestations of this disease and a low degree of emphasis may lead to missed diagnosis, misdiagnosis, and delayed diagnosis. This article summarizes the clinical features, common pathogenic genes and their mutation sites, and diagnosis of four common types of congenital hyperbilirubinemia, i.e., Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome, in order to provide a reference for clinicians.

Efficacy and safety of yimitasvir phospha combined with sofosbuvir in patients with chronic hepatitis C virus infection / 中华传染病杂志

Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.

Change in immune status after antiviral therapy in patients with hepatitis C virus infection / 临床肝胆病杂志

Hepatitis C virus (HCV) infection is a global public health issue.At present,pegylated interferon (IFN) combined with ribavirin is the major therapeutic regimen for anti-HCV treatment in China,but this regimen cannot achieve ideal sustained virologic response.Direct-acting antivirals (DAA) have achieved marked clinical effects in the treatment of patients with hepatitis C.This article briefly describes the change in immune status after anti-HCV treatment from the three aspects of innate immunity,adaptive immunity,and cytokines/ chemokines.The analysis shows that HCV patients have complex immunoregulation,and the results vary from one study to another.In general,the expression of NK cell surface receptor and its function tend to recover and may even recover to a normal state.IFN treatment cannot restore the function of virus-specific CD8 + T lymphocytes,while the change in cytotoxic T lymphocytes after DAA treatment has not been clarified.Further studies are needed to elucidate the long-term effect of DAA on cvtokines and chemokines.

Route of metastasis of primary hepatic carcinoma from the perspective of anatomy / 临床肝胆病杂志

Intrahepatic or extrahepatic metastasis of primary hepatic carcinoma (PHC) often occurs via various routes,which leads to treatment failure or recurrence after treatment.Almost 90％ of PHC patients die of metastasis.This article summarizes the common routes of PHC metastasis,including blood channel (the portal vein and the hepatic vein),lymphatic channel,biliary tract,direct invasion of adjacent organs,and implantation metastasis,and analyzes the basic features,clinical significance,and future research interests of each route of metastasis.It is pointed out that these routes are closely associated with anatomy.

Influencing factors for the therapeutic effect of direct-acting antiviral agents in hepatitis C / 临床肝胆病杂志

The application of direct-acting antiviral agents significantly increases the rate of sustained virologic response in patients with hepatitis C,but there are still some patients who have no response during treatment or experience recurrence after treatment.Related influencing factors are research hotspots at present.This article reviews the influencing factors for the therapeutic effect of direct-acting antiviral agents in hepatitis C from the perspectives of HCV resistance-related mutations,HCV genotypes,viral load,degree of liver lesions,and drug combination,in order to provide a reference for clinical prevention and treatment of chronic hepatitis C.

Current Research on acute-on-chronic liver failure: a comparison between Eastern and Western countries / 临床肝胆病杂志

Acute-on-chronic liver failure (ACLF) is the most complicated form of liver failure among various types of liver failure. There are certain differences in the conception, etiology, and pathogenesis of ACLF between different regions. In recent years, ACLF has attracted attention of hepatologists all over the world, and some important progress has been made, which contributes to academic communication on ACLF, an early consensus on the diagnosis and treatment of ACLF, and eventually an increased survival rate in patients. This paper reviews the differences in conception between the Eastern and Western parts of the world, pathogenesis, treatment, and prognostic judgment of ACLF.

Protective effects and possible mechanisms of hepatic fibrosis against APAP-induced lethal injury / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the protective effects of hepatic fibrosis against a lethal dose of acetaminophen (APAP) and its underlying mechanisms using a carbon tetrachloride (CCl4)-induced mouse model of fibrosis.</p><p><b>METHODS</b>The experimental model of hepatic fibrosis was established by intraperitoneal injection of CC14 (in mineral oil), twice a week for 6 weeks; mice given a 6-week course of mineral oil injections served as normal controls. At the end of fibrosis induction, the expmimental (Fib group) and control (Norm group) mice were challenged with APAP (1 g/kg). Sera and liver tissues were harvested for analyses.To assess tolerance of the normal and fibrotic mice to the lethal dose of APAP, the survival rate,serum alanine aminotransferase (sALT) levels and hepatic histopathological changes were compared before and after the acute APAP challenge.HMGB 1 expression was analyzed by immunohistochemistry.One-way ANOVA test and Newman-Keuls test were used in statistical analysis.</p><p><b>RESULTS</b>The fibrotic liver was tolerant to the lethal dose of APAP,as evidenced by:(1) significantly higher survival rate in the Fib ± APAP group (80% vs. Norm+APAP group: 0%); (2) markedly lower sALT levels in the Fib+APAP group (6 437 ± 1 913 U/L vs. 12 456 ± 3 441 U/L), P=0.022; (3) remarkably well-preserved liver architecture in the Fib+APAP group.Immunohistochemical analysis showed high HMGB1 expression and cytoplasmic translocation in the Norm+APAP group,which was absent in the Fib+APAP group.</p><p><b>CONCLUSIONS</b>CCl4-induced liver fibrosis protects mice against lethal dose of APAP, Possibly by a mechanism involving inhibition of the cytoplasmic translocation of HMGB1.</p>

Role of endoplasmic reticulum stress in D-GalN/LPS-induced acute liver failure / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the role of endoplasmic reticulum stress (ERS) in acute liver failure (ALF) using a mouse model of D-Galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF.</p><p><b>METHODS</b>The ALF model was established by administering intraperitoneal (i.p.) injections of D-Ga1N (700 mg/kg) and LPS (10 mug/kg) to six C57BL/6 mice. Three of the modeled mice were also administered 4-phenylbutyrate (4-PBA; 100 mg/kg i.p.) at 6 hours before the onset of ALF and served as the intervention group. Non-modeled mice served as controls. All mice were analyzed by western blotting and qRT-PCR to determine the expression levels of ERS-related proteins in liver tissue. Liver function was assessed by measuring levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum. Extent of injury to the liver tissue was assessed by hematoxylin-eosin staining and histological analysis. qRT-PCR was also used to detect differences in expression of inflammation-related genes, and western blotting was also used to detect differences in expression of the apoptosis related protein Caspase-3.The extent of apoptosis in liver tissue was assessed by TUNEL assay.</p><p><b>RESULTS</b>The ERS markers GRP78 and GRP94 showed increased expression at both the gene and protein levels which followed progression of ALF. The ERS effector proteins XBP-1, ATF-6 and IRE 1 a involved in the unfolded protein response were activated in the early stages of ALF, and the ERS-induced apoptosis regulators Caspase-12 and CHOP were activated in the late stage of ALF. Inhibition of ERS by 4-PBA intervention protected against injury to liver tissue and function, as evidenced by significantly lower levels of serum ALT and AST and a remarkably decreased extent of histological alterations. Furthermore, the inhibition of ERS suppressed expression of the proinflammatory cytokines TNFa, IL-6 and IL-1 β, and reduced the extent of hepatocyte apoptosis.</p><p><b>CONCLUSION</b>ERS is activated in the mouse model of D-GalN/LPS-induced ALF. Inhibition of ERS may be protective against liver injury and the mechanism of action may involve reductions in inflammatory and apoptotic factors and/or signaling. Therefore, inhibiting ERS may represent a novel therapeutic approach for treating ALF.</p>

Protective role of PTEN inhibition against liver ischemia-reperfusion injury in mice and its underlying mechanisms / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate whether inhibition of phosphatase and tensin homologue deleted on chromosome ten (PTEN) is protective against liver ischemia-reperfusion injury (IRI) in mice and to explore its possible mechanism.</p><p><b>METHODS</b>Liver IRI was established in C57BL6/J mice by inducing 90 minutes of ischemia in the left/middle liver lobe followed by 6 hours of reperfusion. To investigate the role of PTEN in hepatic IRI, a subset of these mice received pre-treatment with the specific PTEN inhibitor bpv(HOpic), which was injected intraperitoneally at 2 hours prior to the ischemia insult. Serum alanine aminotransferase (sALT) levels were measured and liver histology was assessed in all mice. The levels of pro-inflammatory cytokines IL-12p40 and TNFa were detected by real-time PCR. The expression of p-AKT and p-ERK in liver tissues was analyzed by Western blotting.</p><p><b>RESULTS</b>The IRI group pre-treated with bpv(HOpic) showed significantly lower sALT values (3 075.0 +/- 807.4 U/L vs. IRI without pre-treatment: 11 460.0 +/- 1 783.0 U/L, P less than 0.01) and more well-preserved liver architecture. The expression of pro-inflammatory cytokines was inhibited markedly by the administration of bpv(HOpic); for IRI without pre-treatment vs.IRI pre-treated with bpv(HOpic), the IL-12 levels were 1.12 +/- 0.11 vs .0.55 +/- 0.13 ( P less than 0.01) and the TNFa levels were 1.62 +/- 0.20 vs. 0.35 +/- 0.07 ( P less than 0.01). Western blot analysis showed that the hepatic expression of both p-AKT and p-ERK was enhanced obviously in mice pretreated with the PTEN inhibitor.</p><p><b>CONCLUSION</b>PTEN inhibition alleviates hepatic ischemia-reperfusion injury via the up-regulation of pro-survival signaling mediated by p-AKT and p-ERK as well as the inhibition of hepatic inflammation. PTEN may represent a useful target for the treatment of liver IRI.</p>