Ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China: a CR-HepB-based real-world study / 中华肝脏病杂志

Objective: To understand ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China. Methods: Patients with chronic HBV infection:demographic, virologic, hematologic, blood biochemistry, and antiviral treatment data were extracted from the China Registry of Hepatitis B (CR-HepB) database between 2012 and 2022 for descriptive statistics and change trend analysis. Multiple group comparisons were conducted using the Kruskal Wallis H test, while counting data was compared between groups using χ (2) test. Results: A total of 180 012 patients with chronic HBV infection were included, with a median age of 40 years old, and a male proportion accounting for 60.2%. The HBeAg positive rate was 43.3%. Over time, the median age of new patients each year increased from 39 to 47 years, while the HBeAg positive rate decreased from 51.3% to 32.8%. The initial diagnosis of patients was mainly CHB (71.4%), followed by hepatitis B cirrhosis (11.8%), inactive HBsAg carrier status (10.6%), and chronic HBV carrier status (6.2%). Among the newly registered patients every year from 2012 to 2022, the proportion of hepatitis B cirrhosis remained stable, but after 2019, the proportion of CHB increased and the proportion of other diagnoses decreased. The proportion of patients with cirrhosis increased with age in different age groups, with 3.5%, 19.3%, and 30.4% in the < 40, 40-69, and≥70 age groups, respectively. The proportion of women in patients with cirrhosis also increased with age, from 16.1% in those < 30 years old to 44.3% in those≥80 years old. From 2012 to 2022, the proportion of patients receiving first-line nucleos(t)ide analog antiviral treatment increased year by year, from 51.0% in 2012-2013 to 99.8% in 2022. Conclusion: The CR-HepB registration data reflect the changes in clinical characteristics and antiviral treatment patterns in patients with chronic HBV infection in China over the past ten years and can thus provide a reference to promote hepatitis B diagnosis and treatment practice, as well as scientific research.

Application of different prognostic scores in liver transplantation decision-making for acute-on-chronic liver failure / 中华肝脏病杂志

Objective: To compare the impact of different prognostic scores in patients with acute-on-chronic liver failure (ACLF) in order to provide treatment guidance for liver transplantation. Methods: The information on inpatients with ACLF admitted at Beijing You'an Hospital Affiliated to Capital Medical University and the First Affiliated Hospital of Zhejiang University School of Medicine from January 2015 to October 2022 was collected retrospectively. ACLF patients were divided into liver transplantation and non-liver transplantation groups, and the two groups prognostic conditions were followed-up. Propensity score matching was carried out between the two groups on the basis of liver disease (non-cirrhosis, compensated cirrhosis, and decompensated cirrhosis), the model for end-stage liver disease incorporating serum sodium (MELD-Na), and ACLF classification as matching factors. The prognostic condition of the two groups after matching was compared. The difference in 1-year survival rate between the two groups was analyzed under different ACLF grades and MELD-Na scores. The independent sample t-test or rank sum test was used for inter-group comparison, and the χ (2) test was used for the comparison of count data between groups. Results: In total, 865 ACLF inpatients were collected over the study period. Of these, 291 had liver transplantation and 574 did not. The overall survival rates at 28, 90, and 360 days were 78%, 66%, and 62%, respectively. There were 270 cases of matched ACLF post-liver transplantation and 270 cases without ACLF, in accordance with a ratio of 1:1. At 28, 90, and 360 days, patients with non-liver transplantation had significantly lower survival rates (68%, 53%, and 49%) than patients with liver transplantation (87%, 87%, and 78%, respectively; P < 0.001). Patients were classified into four groups according to the ACLF classification criteria. Kaplan-Meier survival analysis showed that the survival rates of liver transplantation and non-liver transplantation patients in ACLF grade 0 were 77.2% and 69.4%, respectively, with no statistically significant difference (P = 0.168). The survival rate with an ACLF 1-3 grade was significantly higher in liver transplantation patients than that of non-liver transplantation patients (P < 0.05). Patients with ACLF grades 1, 2, and 3 had higher 1-year survival rates compared to non-liver transplant patients by 50.6%, 43.6%, and 61.7%, respectively. Patients were divided into four groups according to the MELD-Na score. Among the patients with a MELD-Na score of < 25, the 1-year survival rates for liver transplantation and non-liver transplantation were 78.2% and 74.0%, respectively, and the difference was not statistically significant (P = 0.149). However, among patients with MELD-Na scores of 25-30, 30-35, and≥35, the survival rate was significantly higher in liver transplantation than that of non-liver transplantation, and the 1-year survival rate increased by 36.4%, 54.9%, and 62.5%, respectively (P < 0.001). Further analysis of the prognosis of patients with different ACLF grades and MELD-Na scores showed that ACLF grades 0 or 1 and MELD-Na score of < 30 had no statistically significant difference in the 1-year survival rate between liver transplantation and non-liver transplantation (P > 0.05), but in patients with MELD-Na score≥30, the 1-year survival rate of liver transplantation was higher than that of non-liver transplantation patients (P < 0.05). In the ACLF grade 0 and MELD-Na score of≥30 group, the 1-year survival rates of liver transplantation and non-liver transplantation patients were 77.8% and 25.0% respectively (P < 0.05); while in the ACLF grade 1 and MELD-Na score of≥30 group, the 1-year survival rates of liver transplantation and non-liver transplantation patients were 100% and 20.0%, respectively (P < 0.01). Among patients with ACLF grade 2, the 1-year survival rate with MELD-Na score of < 25 in patients with liver transplantation was 73.9% and 61.6%, respectively, and the difference was not statistically significant (P > 0.05); while in the liver transplantation patients group with MELD-Na score of ≥25, the 1-year survival rate was 79.5%, 80.8%, and 75%, respectively, which was significantly higher than that of non-liver transplantation patients (36.6%, 27.6%, 15.0%) (P < 0.001). Among patients with ACLF grade 3, regardless of the MELD-Na score, the 1-year survival rate was significantly higher in liver transplantation patients than that of non-liver transplantation patients (P < 0.01). Additionally, among patients with non-liver transplantation with an ACLF grade 0~1 and a MELD-Na score of < 30 at admission, 99.4% survived 1 year and still had an ACLF grade 0-1 at discharge, while 70% of deaths progressed to ACLF grade 2-3. Conclusion: Both the MELD-Na score and the EASL-CLIF C ACLF classification are capable of guiding liver transplantation; however, no single model possesses a consistent and precise prediction ability. Therefore, the combined application of the two models is necessary for comprehensive and dynamic evaluation, but the clinical application is relatively complex. A simplified prognostic model and a risk assessment model will be required in the future to improve patient prognosis as well as the effectiveness and efficiency of liver transplantation.

Nonalcoholic fatty liver disease and bilirubin: correlation, mechanism, and therapeutic perspectives / 中华肝脏病杂志

Non-alcoholic fatty liver disease (NAFLD) is a metabolic-related disorder induced by multiple factors and mainly characterized by excessive fat buildup in hepatocytes. With the consumption of a Western-style diet and obesity prevalence in recent years, the incidence of NAFLD has gradually increased, becoming an increasingly serious public health problem. Bilirubin is a heme metabolite and a potent antioxidant. Studies have demonstrated that bilirubin levels have an inverse correlation with the incidence rate of NAFLD; however, which form of bilirubin plays the main protective role is still controversial. It is considered that the main protective mechanisms for NAFLD are bilirubin antioxidant properties, insulin resistance reduction, and mitochondrial function. This article summarizes the correlation, protective mechanism, and possible clinical application of NAFLD and bilirubin.

Study of clinical characteristics in patients with gp210 antibody-positive primary biliary cholangitis / 中华肝脏病杂志

Objective: To analyze the clinical characteristics and prognostic value of liver function in a large samples of patients with anti-glycoprotein 210 (gp210 antibody) positive primary biliary cholangitis (PBC). Methods: A retrospective study was performed on 931 PBC cases in Beijing You'an Hospital affiliated to Capital Medical University from 2010 to 2019. According to the detection of gp210 antibody, 318 cases were divided into gp210 antibody positive group (positive group) and 613 cases were divided into gp210 antibody negative group (negative group). The differences in demographic, medical history, clinical indicators, B-ultrasound and pathological indicators as well as the histopathological basis were compared between the two groups. SPSS 16.0 software was used for statistical analysis. Measurement data were analyzed by t-test or rank sum test, and enumeration data by χ2 test. Multivariate analysis was used for logistic test, and and survival analysis was used for prognosis. Results: The positive and the negative groups were compared. The ratio of male to female was significantly higher in positive than negative group (1:5.35 vs. 1:9.73, P＜0.05), and the difference was statistically significant. The proportion of hormone use in history of past diagnosed and treated was higher in positive than negative group (12.9% vs. 3.47%, P＜0.05), and the difference was statistically significant. The detection of biochemical indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT) were higher in positive than the negative group (51.1 U/L vs. 41.1 U/L, 62.6 U/L vs. 49.6 U/L, 24.1 μmol/L vs. 17.9 μmol/L, 228.3 U/L vs. 169.6 U/L, 203.9 U/L vs. 147.6 U/L), (P＜0.05), and the differences were statistically significant. Antinuclear antibody (ANA)-positive rate, high titer ratio and immunoglobulin G (IgG) levels were higher in positive than negative group (95.2% vs. 81.6%, 69.7% vs. 48.8%, 17.2 g/L vs. 16.2 g/L), (P＜0.05), and the differences were statistically significant. The incidence of liver failure was higher in positive than negative group (P＜0.05). CK7 and inflammation score were higher in positive group than negative group in liver histopathological observations (0.83±0.53 vs. 0.28±0.47; 1.06±0.39 vs. 0.54±0.65), (P＜0.05), and the differences were statistically significant. Conclusion: The illness condition of patients with gp210 antibody positive PBC is more severe than patients with gp210 antibody negative PBC, and the incidence of liver failure is significantly increased. Cholangiocytes may be the histopathological basis of the clinical characteristics of gp210 antibody positive PBC patients.

Liver fibrosis inhibits lethal injury through D-galactosamine/lipopolysaccharide-induced necroptosis / 中华肝脏病杂志

Objective: To explore the new mechanism of liver fibrosis through D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced necroptosis as an entry point to inhibit lethal injury. Methods: The carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established. At 6 weeks of fibrosis, the mice were challenged with a lethal dose of D-GalN/LPS, and the normal mice treated with the same treatment were used as the control. The experiment was divided into four groups: control group (Control), acute injury group (D-GalN/LPS), liver fibrosis group (Fib), and liver fibrosis + acute challenge group (Fib + D-GalN/LPS). Quantitative PCR and immunofluorescence were used to analyze the expression of necroptosis key signal molecules RIPK1, RIPK3, MLKL and/or P-MLKL in each group. Normal mice were treated with inhibitors targeting key signaling molecules of necroptosis, and then given an acute challenge. The inhibitory effect of D-GalN/LPS-induced-necroptosis on acute liver injury was evaluated according to the changes in transaminase levels and liver histology. Liver fibrosis spontaneous ablation model was established, and then acute challenge was given. Necroptosis key signal molecules expression was analyzed in liver tissue of mice in each group and compared by immunohistochemistry. The differences between groups were compared with t-test or analysis of variance. Results: Quantitative PCR and immunofluorescence assays result showed that D-GalN/LPS-induced significant upregulation of RIPK1, RIPK3, MLKL and/or P-MLKL. Necroptosis key signal molecules inhibition had significantly reduced D-GalN/LPS-induced liver injury, as manifested by markedly reduced serum ALT and AST levels with improvement in liver histology. Necroptosis signaling molecules expression was significantly inhibited in fibrotic livers even under acute challenge conditions. Additionally, liver fibrosis with gradual attenuation of fibrotic ablation had inhibited D-GalN/LPS-induced necroptosis. Conclusion: Liver fibrosis may protect mice from acute lethal challenge injury by inhibiting D-GalN/LPS-induced necroptosis.

Role of lymphocytes in the pathogenesis of autoimmune hepatitis / 中华肝脏病杂志

In recent years, the number of autoimmune hepatitis cases in the world has shown a significant upward trend, but its etiology and pathogenesis is still unclear. At present, it is generally considered to be caused by abnormal immune regulation mechanism of the body, especially the lymphocytes and their cytokines, which has attracted widespread concern and thus is reviewed here.

Interpretation of the 2022 edition guidelines for hepatolenticular degeneration diagnosis and treatment / 中华肝脏病杂志

In order to help liver disease-related clinicians make rational decisions, the Inherited and Metabolic Liver Disease Cooperative Group of Hepatology Branch of Chinese Medical Association released the 2022 edition guidelines for hepatolenticular degeneration diagnosis and treatment. This article introduces the ten highlights of this guideline from the aspects of epidemiology, pathogenesis, clinical characteristics, laboratory tests, diagnosis, treatment, monitoring, and so forth, with practicality and operability as prominent features.

Interpretation of the American College of Gastroenterology clinical guidelines for acute-on-chronic liver failure / 中华肝脏病杂志

In January 2022, the American College of Gastroenterology released its first clinical guidelines, integrating the latest research, summarizing the three current definitions characteristics, and proposing recommendations and core viewpoints with important clinical practice value to guide diagnosis, treatment, and management of acute-on-chronic liver failure. This article interprets and summarizes the highlights of the guideline, raises controversial issues, and suggests directions for future research.

Management of hepatolenticular degeneration during pregnancy / 中华肝脏病杂志

Hepatolenticular degeneration (Wilson's disease, WD) is a kind of autosomal recessive genetic disease characterized by disorders of copper metabolism. It is caused by mutations in the ATP7B gene, resulting in impaired excretion of copper into the bile, and then pathological deposition in the liver, brain, and other organs. Early diagnosis and treatment can significantly improve the prognosis of patients with WD. However, there is still no clear consensus on the treatment and management of WD during pregnancy. Herein, the clinical management of WD during pregnancy is summarized for clinicians' reference.

Clinical application of serum Golgi protein 73 in patients with chronic liver diseases / 中华肝脏病杂志

Golgi protein 73 (GP73) is a transmembrane protein on the Golgi apparatus and can be cut and released into the blood. In recent years, an increasing number of clinical studies have shown that the elevated serum GP73 level is closely related to liver diseases. And thus GP73 is expected to be used as a new serum marker for assessing progress of chronic liver diseases. Herein, the clinical application of serum GP73 in chronic hepatitis, liver fibrosis, liver cirrhosis and hepatocellular carcinoma with different etiologies was reviewed based on available literatures; and a research outlook in this field is made.

Protective Effect of Ganshuang Granules () on Liver Cirrhosis by Suppressing Regulatory T Cells in Mouse Model / 中国结合医学杂志

OBJECTIVE@#To investigate the potential antifibrotic mechanisms of Chinese medicine Ganshuang Granules (, GSG) and to provide clinical therapeutic evidence of its effects.@*METHODS@#A cirrhotic mouse model was established by intraperitoneally injecting a mixture of CCl (40%) and oil (60%) at 0.2 mL per 100 g of body weight twice a week for 12 weeks. After 12-week modeling, GSG was intragastric administrated to the mice for 2 weeks, and the mice were divided into low-, medium- and high-dose groups at doses of 1, 2 and 4 g/(kg·day), respectively. Liver morphology changes were observed using Masson's trichrome staining and B-ultrasound. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hyaluronic acid (HA) in serum were detected using an automatic biochemistry analyzer. The expressions of desmin, smooth muscle actin (SMA) and Foxp3 in liver were detected by immunoflfluorescence. The regulatory T cell (Treg) frequency was determined through flflow cytometry analysis. Collagen-I, SMA, IL-6, tumor necrosis factor α (TNF-α), interleukin (IL)-1β and transforming growth factor β1 (TGF-β1) expression levels were measured using quantitative polymerase chain reaction (qPCR).@*RESULTS@#Masson's staining result showed fewer pseudolobule structures and fibrous connective tissue in the GSG-treatment groups than in the spontaneous recovery group. Ultrasonography showed that GSG treatment reduced the number of punctate hyperechoic lesions in mice cirrhotic livers. The serum ALT, AST, HA levels were significantly ameliorated by GSG treatment (ALT: F=8.104, P=0.000; AST: F=7.078, P=0.002; and HA: F=7.621, P=0.001). The expression levels of collagen-I and SMA in the cirrhotic livers were also attenuated by GSG treatment (collagen-I: F=3.938, P=0.011; SMA: F=4.115, P=0.009). Tregs, which were elevated in the fibrotic livers, were suppressed by GSG treatment (F=8.268, P=0.001). The expressions of IL-6, TNF-α and IL-1β increased, and TGF-β levels decreased in the cirrhotic livers after GSG treatment (IL-6: F=5.457, P=0.004; TNF-α: F=6.023, P=0.002; IL-1β: F=6.658, P=0.001; and TGF-β1: F=11.239, P=0.000).@*CONCLUSIONS@#GSG promoted the resolution/regression of cirrhosis and restored liver functions in part by suppressing Treg cell differentiation, which may be mediated by hepatic stellate cells.

Prevalence of nutritional risk among in-patients with liver diseases in Beijing, China / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the prevalence of nutritional risk and malnutrition among in-patients with liver diseases in Beijing, China, and to evaluate the relationship between nutritional risk and prognosis.</p><p><b>METHODS</b>A total of 331 in-patients with liver diseases under care at the Artificial Liver Center of Beijing Youan Hospital were consecutively enrolled for study between April 2012 and December 2012. Nutritional status was determined by calculating each patient's ratio of real weight to clinically ideal weight, the triceps skin fold (TSF), and the mid-upper arm muscle circumference (MAMC). Nutritional risk was estimated using the Nutritional Risk Screening questionnaire 2002 (NRS-2002). In addition, each patient's Child-Pugh stage, body mass index (BMI), power of gripping, serum albumin and pre-albumin levels, lymphocyte count, hospital length of stay, complications, alcoholism history, and outcome after discharge were recorded for analysis.</p><p><b>RESULTS</b>One-hundred-and-thirteen of the patients (34.1%) were defined as at nutritional risk upon hospital admission. The ratio of nutritional risk was lowest in patients with chronic hepatitis (17.0%) and highest in patients with acute on chronic liver failure (56.5%). The ratios of malnutrition evaluated by TSF and MAMC were 36.9% and 38.7%, respectively. Among the patients with liver cirrhosis or hepatocellular carcinoma, the ratio of Child-Pugh stage C was higher for individuals defined as at nutritional risk than for those without. When TSF-based ratio of malnutrition was higher for individuals with a history of alcoholism than for those without. BMI, power of gripping, serum albumin level, serum pre-albumin level, and lymphocyte count were all lower for individuals defined as at nutritional risk than for those without. Hospital stay, ratio of complication onset, and ratio of death were all higher for individuals defined as at nutritional risk than for those without.</p><p><b>CONCLUSION</b>TSF and MAMC can be used to evaluate the nutritional status of in-patients with liver diseases. Patients with nutritional risk (as determined by the NRS-2002) have poorer prognosis and may benefit from nutritional intervention.</p>

Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To determine the mechanism underlying the therapeutic activities of glycogen synthase kinase 3b (GSK3b) against hepatic ischemia-reperfusion (H-IR) injury by investigating the inhibitive effects of GSK3b on inflammation mediated by Toll-like receptor 4 (TLR4).</p><p><b>METHODS</b>C57BL/6 male mice were subjected to 90 min of warm liver cephalad lobe ischemia, followed by reperfusion for various lengths of time. The mice were divided into three groups: the H-IR untreated model (control group), and the H-IR inflammation-induced models that received an intraperitoneal injection of purified lipopolysaccharide (LPS) endotoxin alone (inflammation group) or with pretreatment of the SB216763 GSK3b-specific inhibitor (intervention group). To create a parallel isolated cell system for detailed investigations of macrophages, marrow-derived stem cells were isolated from femurs of the H-IR control group of mice and used to derive primary macrophages. The cells were then divided into the same three groups as the whole mouse system: control, LPS-induced inflammation model, and inflammation model with SB216763 intervention. Differential expressions of inflammation-related proteins and genes were detected by Western blotting and real-time quantitative PCR, respectively.</p><p><b>RESULTS</b>The phosphorylation levels of ERK, JNK and p38 MAPK were induced in liver at 1 h after reperfusion, but then steadily decreased and returned to baseline levels by 4 h after reperfusion. In addition, the phosphorylation levels of ERK and JNK were induced in macrophages at 15 min after LPS stimulation, while the phosphorylation level of p38 MAPK was induced at 1 h; SB216763 pretreatment suppressed the LPS-stimulated ERK, JNK and p38 phosphorylation in macrophages. In the mouse model, GSK3b activity was found to promote the gene expression of anti-inflammatory cytokine IL-10 (control: 0.21 ± 0.08, inflammation: 0.83 ± 0.21, intervention: 1.76 ± 0.67; F = 3.16, P = 0.027) but to significantly inhibit the gene expression of pro-inflammatory cytokines IL-12 (control: 0.11 ± 0.05, inflammation: 0.85 ± 0.11, intervention: 0.43 ± 0.10; F = 2.67, P = 0.038), TNF-a, (control: 0.052 ± 0.012, inflammation: 8.11 ± 0.98, intervention: 3.9 ± 0.82; F = 4.13, P = 0.016), IL-6 (control: 0.22 ± 0.08, inflammation: 6.37 ± 0.81, intervention: 2.11 ± 0.63; F = 3.21, P = 0.024), and IL-1b (control: 0.12 ± 0.07, inflammation: 2.51 ± 0.62, and intervention: 1.28 ± 0.33; F = 2.22, P = 0.030).</p><p><b>CONCLUSION</b>Inhibition of GSK3b selectively regulates the expression of anti-inflammatory and pro-inflammatory cytokines in liver Kupffer cells (liver macrophages). This process may be one of the mechanisms underlying the ability of GSK3b to ameliorate hepatic ischemia-reperfusion injury, possibly because inhibition of pro-inflammatory cytokines may indirectly mediate liver cell apoptosis.</p>

Entecavir treatment causes injury to the mitochondrial DNA of peripheral blood mononuclear cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>Based on the potential for nucleotide analogues to affect DNA polymerase-gamma, which controls the proliferation of mitochondria, this study aimed to determine whether long-term treatment with entecavir can cause damage to mitochondrial (mt)DNA in the peripheral blood mononuclear cells (PBMCs) of patients with chronic hepatitis B (CHB).</p><p><b>METHODS</b>Patients with CHB were divided into three groups according to their history of treatment type and duration: (1) entecavir monotherapy for 2 years, n = 17; (2) entecavir monotherapy for 3 years, n = 17; (3) non-antiviral treatment as control, n = 18. PBMCs were isolated and used to assess the mtDNA content by quantitative real-time PCR of mitochondria-specific genes. Plasma malonaldehyde (MDA) and F2-isoprostanes were measured by enzyme linked immunosorbent assay. Plasma total antioxidant capacity (TAOC) was detected by spectrophotometry.</p><p><b>RESULTS</b>The relative quantity (RQ; of mtDNA to nuclear (n)DNA) was significantly lower in the 3-year treatment group (0.5+/-0.3) than in the control group (1.4+/-1.2; F = 5.233, P = 0.009). The RQ was also significantly lower in the 2-year treatment group (0.4+/-0.2) than in the control group (P = 0.004). The level of F2-isoprostanes (ng/mL) was significantly lower in the 3-year treatment group (1.2+/-0.5) than in the control group (3.6+/-2.9, P = 0.002) or the 2-year treatment group (2.4+/-1.3, P = 0.007). The TAOC was significantly different when compared among all three groups (F = 4.326, P = 0.019). The TAOC (IU/mL) in the 3-year treatment group (2.6+/-1.2) was significantly lower than in the control group (5.0+/-3.0 P = 0.005), but was not significantly different than that for the 2-year group (3.2+/-1.6, P = 0.227). The levels of MDA were not significantly different between any of the groups (F = 0.291, P = 0.749).</p><p><b>CONCLUSION</b>Long-term treatment with entecavir, up to 3 years, leads to decreased mtDNA content in PBMCs. Since no clinical manifestations of mtDNA toxicity were observed, the consequent damage to the mitochondrial function may be compensated for by yet unknown mechanisms.</p>

Changing characteristic of blood coagulation factors and their correlation with blood coagulation status in different hepatic diseases / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the correlation between pro coagulation factors and anti-coagulation factors synthesized by the liver, and the correlation between fibrin degradation products (FDP) and D-dimer (D-D) concentration and coagulation proteins synthesized by extra-hepatic tissues, in different liver diseases; to explore the relationship between coagulation and bleeding in hepatic diseases.</p><p><b>METHODS</b>Chronic hepatitis B (CHB) patients, CHB-related liver cirrhosis patients, CHB-related liver failure patients and healthy (normal) controls were selected for study and provided blood samples for analysis. The activity of coagulation factors (F) II, V, VII, VIII, IX, X, XI, and XII was detected using the one-stage clotting method. Coagulogram analysis, including activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT), was conducted by the solidification method. Antithrombin III (AT-III) and protein C (PC) activities were measured by chromogenic substrate assay. FDP concentration was detected using immunoturbidimetry. Tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), von Willebrand factor (vWF), and tissue factor (TF) concentrations were measured by enzyme-linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>With the exception of FVIII, coagulation factors and anticoagulant proteins synthesized by the liver were decreased and the coagulogram was extended for all patients. Likewise, the FDP and D-D concentrations were increased in blood. CHB patients, however, presented with increased levels of FVIII, TFPI, TM, vWF, and TF. Pairwise comparison indicated statistical differences existed among CHB, CHB-related liver cirrhosis, and liver failure patients: TFPI: 239.3+/-206.4, 315.0+/-258.6, and 319.5+/-298.1 -- higher than normal control: 104.0+/-87.1, F = 5.453, P less than 0.05; vWF: 70.3+/-29.5, 105.5+/-58.0, and 179.3+/-61.7 -- higher than normal control: 21.9+/-7.2, F = 20.104, P less than 0.05; TF: 85.9+/-85.7, 234.2+/-202.9, and 344.7+/-214.6 -- higher than normal control: 12.8+/-8.1, F = 8.619, P less than 0.05; FVIII: 157.2+/-53.4, 206.9+/-86.9, and 335.7+/-117.7 -- higher than normal control: 105.5+/-46.2, F = 13.418, P less than 0.05.</p><p><b>CONCLUSION</b>In parallel to the progression of liver diseases, pro coagulation and anti-coagulation elements synthesized by the liver were reduced. In contrast, fibrinolysis activity was enhanced, which is expected to lead to an imbalance between blood clotting and anti-clotting factors. This may be an important cause for the bleeding that occurs in end-stage liver disease. Expressions of TFPI, TM, vWF, and TF significantly change in the early stage of liver diseases, as compared to normal (healthy) levels, and may represent a sensitive indicator of vascular injury.</p>

Natural herbal medicine Lianhuaqingwen capsule anti-influenza A (H1N1) trial: a randomized, double blind, positive controlled clinical trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The 2009 influenza A (H1N1) virus infection is associated with the high risk of severe complications and is spreading more rapidly throughout the world than other reported seasonal influenzas. This study aimed to evaluate the efficacy and safety of the nature herbal medicine Lianhuaqingwen capsule (LHC) in patients infected with influenza A (H1N1) virus.</p><p><b>METHODS</b>A total of 244 patients aged 16 - 65 years confirmed with influenza A (H1N1) virus infection by the real time RT-PCR were randomized to one of two treatment groups of 122 patients each. Each group assigned to receive either LHC or Oseltamivir for five days and observation for seven days. The patients were enrolled within 36 hours of illness onset if they had an axillary temperature of ≥ 37.4°C and with at least one of the following symptoms: nasal obstruction, runny nose, cough, sore throat, fatigue, headache, myalgia, chills and sweating. The primary end point was the duration of illness.</p><p><b>RESULTS</b>Of 244 patients, 240 (98.36%) patients with a median age 21 years completed the study between October 24, 2009 and November 23, 2009. There were no significant overall differences between LHC treated and Oseltamivir treated patients in the median duration of illness (LHC 69 hours vs. Oseltamivir 85 hours P > 0.05) or the median duration of viral shedding (LHC 103 hours vs. Oseltamivir 96 hours, P > 0.05). However, it was worthwhile to note that LHC significantly reduced the severity of illness and the duration of symptoms including fever, cough, sore throat, and fatigue (P < 0.05). Both study medications were well tolerated. No drug related serious adverse events occurred during the study.</p><p><b>CONCLUSIONS</b>Compared with Oseltamivir, LHC achieved a similar therapeutic effectiveness reduction of the duration of illness and duration of viral shedding. Therefore, LHC might be an alternative therapeutic measure for influenza A (H1N1) virus infections.</p>

The role of glycogen synthase kinase-3 beta in the pathogenesis of liver ischemia reperfusion injury / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the role of the key intracellular signaling molecule glycogen synthase kinase-3 beta in the mechanism of liver ischemia reperfusion (IR).</p><p><b>METHODS</b>C57BL/6 mice were subjected to 90 min warm liver cephalad lobe ischemia, followed by various length of reperfusion. Experiment groups included sham control group, liver IRI model group and glycogen synthase kinase-3 beta inhibitor-treated group (SB216763 in DMSO, 25 g/kg, i.p, 2 hour prior to the onset of liver ischemia). The expression of glycogen synthase kinase-3 beta protein was analysed by Western blotting. The serum ALT levels were determined to reflect the function of liver. The affected liver lobes were harvested for histology analysis. The inflammatory gene expression was detected by Quantitative PCR.</p><p><b>RESULTS</b>By western blot analysis, we found that ischemia itself activated glycogen synthase kinase-3 beta by a significant decrease of its phosphorylation. Glycogen synthase kinase-3 beta inhibitor SB216763-pretreatment ameliorated the liver damages significantly as compared to the controls (sALT: 2046+/-513 U/L vs 5809+/-1689 U/L, P = 0.0153), and suppressed the gene expressions of IL-12, TNFa, IL-1b and IL-6.</p><p><b>CONCLUSIONS</b>This study demonstrated that the ischemia process modulated liver innate immune activation via a GSK-3-dependent mechanism which favored the development of a pro-inflammation response and lead to liver tissue damages. GSK-3b may be a new therapeutic target to ameliorate liver IRI in transplant patients.</p>

The changes of interdigestive migrating motor complex in rats with acute liver failure / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To observe the changes and characteristics of interdigestive migrating motor complex (MMC) in rat models of acute liver failure.</p><p><b>METHODS</b>30 rat models with acute liver failure were induced with D-galactosamine and another 30 normal rats were used as controls. The indexes of MMC recorded by multi-channel physiological recorder were compared.</p><p><b>RESULTS</b>No significant differences found between the two groups in antral and duodenal MMC cycles and frequencies of duodenal and jejunal MMC III phase. Compared with normal controls, the MMC II phase in the acute liver failure rats was significantly prolonged (t=-3.97, -3.85, P<0.05), the MMC III duration of antrum and duodenum (u=-4.99, t=4.66, P<0.05) was shorter and the MMC III frequency of antrum (u=-4.73, P<0.05) was faster. In addition, the MMC cycle and MMC III phase of jejunum were significantly prolonged (u=-1.63, t=-4.94, P<0.05) and the MMC III phase duration was significantly shorter in the acute liver failure rats (t=5.10, P<0.05).</p><p><b>CONCLUSION</b>Significantly prolonged MMC II phase characterized by migrating clustered contraction, shortened MMC III phase and extended jejunal MMC cycles were probably the major contributors to the gastrointestinal motility disorders in the rats with acute liver failure.</p>

A retrospective study of clinical and pathological spectrum in 91 patients with chronic severe hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>In China, liver failure is also termed as severe hepatitis in whom chronic severe hepatitis B (CSHB) is most common. The aim of this study was to assess whether CSHB based on different liver injury extent can meet the international definition of acute-on-chronic liver failure(ACLF)criteria, according by their clinical and pathological feature.</p><p><b>METHODS</b>A total of 91 patients with CSHB were involved in the study. The clinical findings, laboratory data and liver pathology features were retrospectively analyzed and grouped by hepatitis virus B carrier state (HBC), chronic hepatitis B (CHB) or liver cirrhosis (LC) before they started liver failure.</p><p><b>RESULTS</b>74 out of the 91 patients were male and 17 were female, the mean age was 40.6+/-11.2 years. 9.9%, 7.7% and 82.4% of the patients were based on HBC, CHB and LC respectively. The ages of HBC group were youngest. The mean age of HBC group (years) (25.8+/-6.6) was significantly lower than that of CHB group (36.9+/-9.0) and LC group (42.0+/-10.5)with P values of 0.032 and 0.001 respectively. Most cases presented with sub-acute liver failure characterized by high icterus and ascites. Predisposing factors included exertion, superinfection, virus variation, drugs or alcoholic injury. No difference found between PTA (F = 0.906, P = 0.408) and TBil (F = 0.839, P = 0.436) among the above three groups. The Alb and CHE levels in LC group were (30.3+/-5.1) g/L and (2926.8+/-1471.1) U/L respectively, which were lower than both HBC group [Alb (35.6+/-5.1) g/L, CHE (4363.5+/-2063.2) U/L] and CHB group [Alb (37.4+/-5.0) g/L, CHE (5167.1+/-1522.1) U/L] (F = 9.450; F = 9.297; P value less than 0.01).The level of CHO (1.8+/-1.0) mmol/L in LC group was lower than that of HBC group (2.9+/-1.0mmol/L, P = 0.034), while serum HBV DNA level of HBC group [(6.8+/-1.7) log10copies/ml] was higher than that of LC group [(4.2+/-2.6) log10copies/ml]. The liver tissue in HBC and CHB group showed massive or submassive necrosis which distribute evenly in different parts of liver and similarly in slides, most like acute/subacute severe hepatitis. The chronic lesion was easily covered by extensive necrosis in CSHB based on CHB, with portal fibrosis can be seen by masson stain. Characteristic picture of LC group were massive or submassive necrosis with some nodules were intact or only patchy necrosis of the parenchyma, disparity of extent and stage of necrosis existed in slides, which were the major difference in histopathological change in HBC and CHB group.</p><p><b>CONCLUSION</b>Most of CSHB cases were based on liver cirrhosis, which match with the international definition of ACLF, while small part of CSHB cases based on HBC and CHB are identical to acute/subacute liver failure.</p>

Effects of neurotrophin 3 on interdigestive migrating motor complex in rats with acute liver injury / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the effects of neurotrophin 3(NT-3)on interdigestive migrating motor complex (MMC) in rats with D-galactosamine induced acute liver injury.</p><p><b>METHODS</b>Twenty-four specific pathogen-free purebred rats were equally randomized into control and acute liver injury groups. The control group was injected with equal volume of normal saline via tail vein. Acute liver injury model of the rats was induced by D-galactosamine injection via the tail vein in the acute liver injury group. And the indexes of interdigestive MMC before and after NT-3 injection were recorded by a polygraph and analyzed in model group. The serum NT-3 concentration was assayed in the two groups.</p><p><b>RESULTS</b>There were no significant changes of gastrointestinal MMC cycle and jejunal phase I MMC after NT-3 injection. Compared with the acute liver injury rats before NT-3 injection , the antral phases I, III and IV MMC were significantly prolonged [(577.44 ± 248.60)s vs (343.58 ± 227.30) s, (80.94 ± 21.15) s vs (24.76 ± 7.41) s, (405.69 ± 131.34) s vs (191.67 ± 128.15) s, P < 0.05] and the phase II MMC was shortened [ (883.94 ± 488.50) s vs (1519.00 ± 831.14) s, P < 0.05] in the acute liver injury group. The duodenal phases I, III and IV MMC were significantly prolonged [ (557.63 ± 335.14) s vs (309.46 ± 220.22) s,(75.91 ± 15.75) s vs (31.15 ± 13.67) s, (423.38 ± 135.22) s vs (209.77 ± 123.83) s, P < 0.05] and MMC II phase was shortened [ (748.81 ± 579.69) s vs (1535.86 ± 930.50) s, P < 0.05] in the acute liver injury rats. In addition, the jejunal MMC III and MMC IV phase was significantly prolonged [ (86.58 ± 23.40) s vs (31.41 ± 16.09) s,(385.18 ± 110.02) s vs (220.59 ± 159.30) s, P < 0.05] and phase II MMC was shortened [ (876.89 ± 652.01) s vs (1870.89 ± 1010.35) s, P < 0.05 ] in the acute liver injury rats. The serum NT-3 level was significantly higher in model group than in control group.</p><p><b>CONCLUSION</b>NT-3 could enhance the gastrointestinal motility in acute liver injury rats.</p>