Objective To explore the mechanism by which gentiopicroside (GPS) prevents macrophage-mediated hepatic fibrosis by regulating the macrophage migration inhibitory factor (MIF)-secreted phosphoprotein 1 (SPP1) signaling pathway in hepatic stellate cells. Methods LX-2 cells were divided into control group, transforming growth factor β(TGF-β) group, and TGF-β combined with GPS (25, 50, 100, 150 μmol/mL) groups. Cell proliferation was detected by EDU assay, cell invasion was assessed by Transwell^TM assay, and the protein expressions of α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) were measured by Western blot. M1-type macrophage-conditioned medium (M1-CM) was used to treat LX-2 cells in the TGF-β group and TGF-β combined with GPS group. The concentrations of inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1) in the cell supernatant, as well as cell proliferation, invasion ability, and the expressions of α-SMA and COL1A1 were detected. Bioinformatics analysis was performed to identify the target intersections of GPS, hepatic fibrosis, and macrophage-related genes. Drug affinity responsive target stability (DARTS) experiments and Western blot were used to verify the regulatory effect of GPS on MIF. Furthermore, LX-2 cells were divided into control group, TGF-β group, TGF-β combined with M2-CM group, TGF-β and oe-NC combined with M2-CM group, and TGF-β and oe-MIF combined with M2-CM group to analyze the concentrations of iNOS and Arg1 in the cell supernatant, as well as changes in cell proliferation, invasion, and the expressions of α-SMA and COL1A1. LX-2 cells were also divided into control group, TGF-β group, TGF-β combined with oe-NC group, TGF-β combined with oe-MIF group, and TGF-β and oe-MIF combined with GPS group to determine the protein expressions of MIF and SPP1 by Western blot. A rat model of hepatic fibrosis was constructed to explore the potential therapeutic effects of GPS on hepatic fibrosis in vivo. Results Compared with the control group, the proliferation and invasion abilities of LX-2 cells in the TGF-β group were increased, and the protein expressions of α-SMA and COL1A1 were enhanced. GPS intervention inhibited the proliferation and invasion of LX-2 cells under TGF-β conditions and reduced the expressions of α-SMA and COL1A1. Compared with the control group, the concentration of iNOS in the cell supernatant of the TGF-β group was upregulated, while the concentration of Arg1 was decreased. M1-CM treatment further increased the concentration of iNOS, decreased the concentration of Arg1, and promoted cell proliferation and invasion, as well as upregulated the expressions of α-SMA and COL1A1 on the basis of TGF-β intervention. However, GPS could reverse the effects of M1-CM intervention. Bioinformatics analysis revealed that MIF was one of the target intersections of GPS, hepatic fibrosis, and macrophage-related genes, and GPS could target and inhibit its expression. Compared with the TGF-β group, after M2-CM intervention, the concentration of iNOS in the cell supernatant decreased, the concentration of Arg1 increased, the proliferation and invasion abilities of LX-2 cells were reduced, and the expressions of α-SMA and COL1A1 were weakened. However, overexpression of MIF reversed the effects of M2-CM intervention. Western blot results showed that compared with the control group, the protein expressions of MIF and SPP1 were enhanced in the TGF-β group. Overexpression of MIF further enhanced the expressions of MIF and SPP1, while GPS intervention inhibited the expressions of MIF and SPP1. In the animal experiment, GPS intervention treatment alleviated liver injury in rats with hepatic fibrosis and inhibited the expressions of MIF and SPP1, as well as α-SMA and COL1A1 in liver tissue. Conclusion GPS may prevent macrophage-mediated hepatic fibrosis by inhibiting the MIF-SPP1 signaling pathway in hepatic stellate cells.
Hepatic Stellate Cells/metabolism* ; Signal Transduction/drug effects* ; Macrophage Migration-Inhibitory Factors/genetics* ; Liver Cirrhosis/prevention & control* ; Macrophages/drug effects* ; Iridoid Glucosides/pharmacology* ; Humans ; Cell Proliferation/drug effects* ; Animals ; Cell Line ; Collagen Type I/metabolism* ; Collagen Type I, alpha 1 Chain ; Intramolecular Oxidoreductases/genetics* ; Rats ; Transforming Growth Factor beta/pharmacology* ; Actins/metabolism*

In order to standardize the effective prevention, early screening and diagnosis of the population at risk of primary liver cancer, the Chinese Society of Hepatology and Chinese Medical Association organized the relevant domestic experts to formulate the "Consensus on Secondary Prevention of Primary Liver Cancer (2021 version)," based on the basic, clinical and preventive research progress, combined with the actual situation at home and abroad, so as to provide an important basis for the prevention, screening and early diagnosis of primary liver cancer in the population of chronic liver disease.
Carcinoma, Hepatocellular/prevention & control* ; Consensus ; Gastroenterology ; Humans ; Liver Cirrhosis ; Liver Neoplasms/prevention & control* ; Mass Screening ; Secondary Prevention

Spontaneous bacterial peritonitis (SBP) is defined as bacterial infections that occur in patients with cirrhosis and ascites without any significant intraperitoneal infection, accounting for approximately 10–30% of bacterial infections in hospitalized patients. SBP develops in patients with liver cirrhosis because bacterial translocations are increased by changes in the intestinal bacteria and mucosal barriers. In addition, the decreased host immune response cannot remove the bacteria and their products. The most common cause of SBP is Gram-negative bacteria, such as Escherichia coli and Klebsiella species, and infections by Gram-positive bacteria are increasing. SBP is diagnosed by the presence of >250 polymorphonuclear leukocyte/mm³ in ascites after paracentesis. If SBP is diagnosed, empirical antibiotic therapy should be started immediately. Empirical antibiotic treatment should distinguish between community acquired infections and nosocomial infections. Cirrhotic patients with gastrointestinal bleeding or low ascitic protein concentrations should consider primary prevention and those who recover from SBP should consider secondary prevention. This review describes the pathophysiology, diagnosis, treatment, and prevention of SBP.
Ascites ; Bacteria ; Bacterial Infections ; Community-Acquired Infections ; Cross Infection ; Diagnosis ; Escherichia coli ; Fibrosis ; Gram-Negative Bacteria ; Gram-Positive Bacteria ; Hemorrhage ; Humans ; Klebsiella ; Liver Cirrhosis ; Paracentesis ; Peritonitis* ; Primary Prevention ; Secondary Prevention

INTRODUCTIONHepatic venous pressure gradient (HVPG) measurement is recommended for prognostic and therapeutic indications in centres with adequate resources and expertise. Our study aimed to evaluate the quality of HVPG measurements at our centre before and after introduction of a standardised protocol, and the clinical relevance of the HVPG to variceal bleeding in cirrhotics.

METHODSHVPG measurements performed at Singapore General Hospital from 2005-2013 were retrospectively reviewed. Criteria for quality HVPG readings were triplicate readings, absence of negative pressure values and variability of ≤ 2 mmHg. The rate of variceal bleeding was compared in cirrhotics who achieved a HVPG response to pharmacotherapy (reduction of the HVPG to < 12 mmHg or by ≥ 20% of baseline) and those who did not.

RESULTS126 HVPG measurements were performed in 105 patients (mean age 54.7 ± 11.4 years; 55.2% men). 80% had liver cirrhosis and 20% had non-cirrhotic portal hypertension (NCPH). The mean overall HVPG was 13.5 ± 7.2 mmHg, with a significant difference between the cirrhosis and NCPH groups (p < 0.001). The proportion of quality readings significantly improved after the protocol was introduced. HVPG response was achieved in 28 (33.3%, n = 84) cirrhotics. Nine had variceal bleeding over a median follow-up of 29 months. The rate of variceal bleeding was significantly lower in HVPG responders compared to nonresponders (p = 0.025).

CONCLUSIONThe quality of HVPG measurements in our centre improved after the introduction of a standardised protocol. A HVPG response can prognosticate the risk of variceal bleeding in cirrhotics.

Esophageal and Gastric Varices ; complications ; physiopathology ; Female ; Follow-Up Studies ; Gastrointestinal Hemorrhage ; etiology ; physiopathology ; prevention & control ; Humans ; Hypertension, Portal ; complications ; physiopathology ; Liver Cirrhosis ; complications ; physiopathology ; Male ; Middle Aged ; Portal Pressure ; physiology ; Prognosis ; Retrospective Studies

Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog (HH) signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline (PTX) on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate (PMA) was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen (SEA), and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8 (CCK-8) was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and(or) PTX to detect the transforming growth factor-β gene expression. The mRNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The mRNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells (HSCs). The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway.
Animals ; Antigens, Helminth ; isolation & purification ; pharmacology ; Cell Culture Techniques ; Cell Differentiation ; drug effects ; Cell Line ; Culture Media, Conditioned ; chemistry ; pharmacology ; Gene Expression Regulation ; Hedgehog Proteins ; agonists ; antagonists & inhibitors ; genetics ; immunology ; Hepatic Stellate Cells ; cytology ; drug effects ; metabolism ; Humans ; Liver Cirrhosis ; metabolism ; parasitology ; prevention & control ; Macrophage Activation ; drug effects ; Macrophages ; cytology ; drug effects ; immunology ; Models, Biological ; Monocytes ; cytology ; drug effects ; metabolism ; Pentoxifylline ; pharmacology ; Phosphodiesterase Inhibitors ; pharmacology ; RNA, Messenger ; genetics ; immunology ; Schistosoma japonicum ; chemistry ; Signal Transduction ; Tetradecanoylphorbol Acetate ; pharmacology ; Zinc Finger Protein GLI1 ; genetics ; immunology ; Zygote ; chemistry

OBJECTIVETo evaluate the long-term protection efficacy of neonatal hepatitis B vaccination on chronic hepatitis B (CHB) and liver fibrosis and cirrhosis in adults.

METHODSFrom January to October, 2013, a cross-sectional study was conducted among the participants from Qidong Hepatitis B Intervention Study (QHBIS), who were selected through stratified random sampling. The detections of serum alanine aminotransferase (ALT), HBsAg, anti-HBs, anti-HBc, HBeAg, and anti-HBe were conducted and ultrasonography on liver, gallbladder and spleen was performed for them. The positive rates of each serologic markers, the prevalence of active CHB and liver fibrosis and cirrhosis were calculated, the gender specific differences between vaccination group and control group were compared with Chi-square test.

RESULTSA total of 4 421 participants aged (25.59±1.84) years in vaccination group and 3 880 participants aged (26.61±2.24) years in control group were surveyed. The positive rates of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe were 2.38%, 37.73%, 3.78%, 0.57% and 2.15% in vaccination group, and 9.02%, 29.41%, 16.83%, 2.73% and 8.87% in control group, respectively, the differences between two groups were statistically significant (all P<0.05). The prevalence of active CHB and liver fibrosis and cirrhosis were 0.45% and 0.16% in vaccination group, 1.29% and 0.39% in control group, the differences between two groups were statistically significant (P<0.05). The active CHB prevalence was lower in females than in males in both vaccination group and control group (P<0.05). The liver fibrosis and cirrhosis prevalence was lower in females than in males in control group (P<0.05); whereas, no statistical significant difference in liver fibrosis & cirrhosis prevalence between males and females was found in vaccination group (P>0.05).

CONCLUSIONSProtection conferred by neonatal hepatitis B vaccination could last to marrying age. The gender specific difference in protection efficacy needs further study.

Adult ; China ; Cross-Sectional Studies ; Female ; Hepatitis B Antibodies ; blood ; Hepatitis B Surface Antigens ; blood ; Hepatitis B Vaccines ; therapeutic use ; Hepatitis B virus ; Hepatitis B, Chronic ; prevention & control ; Humans ; Liver Cirrhosis ; Male ; Prevalence ; Vaccination ; statistics & numerical data

With recent advances in molecular and genomic investigations, the impact of hepatitis B viral and host factors on the progression of chronic HBV infection has been explored. For viral factors, hepatitis B viral load is a strong predictor for liver disease progression. Hepatitis B viral kinetics appear to be important for successful anti-viral therapy. Serum HBsAg level serves as a complementary marker to viral load for the prediction of HBV-related adverse outcomes in patients with low viral load. In those with low viral load, high serum HBsAg level is associated with higher risks of cirrhosis and HCC. Hepatitis B core-related antigen (HBcrAg) induces host immune responses, and the reduction of the HBcrAg level as well as the increment of total anti-HBc level are significantly associated with favorable outcomes. HBV genotypes (genotype C/D) and mutants (basal core promoter and deletion mutation in pre-S genes) are well known viral genetic markers to predict disease progression. For host factors, serum inflammatory biomarkers have been developed to evaluate the HBV-associated hepatic necroinflammation and fibrosis. Host single nucleotide polymorphism on sodium taurocholate cotransporting polypeptide (NTCP, an HBV entry receptor) may be associated with a decreased risk for cirrhosis and HCC. In conclusion, patients with chronic hepatitis B should be evaluated with relevant viral and host markers to identify those who are at a higher risk of liver disease progression and then receive timely antiviral therapy.
Biomarkers/*blood ; DNA, Viral/blood ; Hepatitis B Surface Antigens/blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications/*diagnosis/prevention & control ; Humans ; Liver Cirrhosis/etiology ; Organic Anion Transporters, Sodium-Dependent/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Symporters/genetics

Mesothelial cells (MCs) cover the surface of visceral organs and the parietal walls of cavities, and they synthesize lubricating fluids to create a slippery surface that facilitates movement between organs without friction. Recent studies have indicated that MCs play active roles in liver development, fibrosis, and regeneration. During liver development, the mesoderm produces MCs that form a single epithelial layer of the mesothelium. MCs exhibit an intermediate phenotype between epithelial cells and mesenchymal cells. Lineage tracing studies have indicated that during liver development, MCs act as mesenchymal progenitor cells that produce hepatic stellate cells, fibroblasts around blood vessels, and smooth muscle cells. Upon liver injury, MCs migrate inward from the liver surface and produce hepatic stellate cells or myofibroblast depending on the etiology, suggesting that MCs are the source of myofibroblasts in capsular fibrosis. Similar to the activation of hepatic stellate cells, transforming growth factor β induces the conversion of MCs into myofibroblasts. Further elucidation of the biological and molecular changes involved in MC activation and fibrogenesis will contribute to the development of novel approaches for the prevention and therapy of liver fibrosis.
Epithelial Cells/*physiology ; Epithelium/metabolism ; Hepatic Stellate Cells/*physiology ; Humans ; Liver/*cytology/injuries/*physiology ; Liver Cirrhosis/etiology/prevention & control ; Liver Regeneration/*physiology ; Mesenchymal Stromal Cells/physiology ; Myofibroblasts/physiology

Recent studies suggest that liver cirrhosis is reversible after administering oral nucleos(t)ide analogue therapy to patients with hepatitis B virus (HBV) infection. However, few studies have addressed whether esophageal varices can regress after such therapy. We report a case of complete regression of esophageal varices during entecavir therapy in patients with HBV-related liver cirrhosis, suggesting that complications of liver cirrhosis such as esophageal varices can regress after the long-term suppression of HBV replication.
Abdomen/diagnostic imaging ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Esophageal and Gastric Varices/complications/prevention & control ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/complications/*drug therapy/virology ; Humans ; Liver Cirrhosis/*diagnosis/etiology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Ultrasonography

BACKGROUND/AIMS: This study aimed to evaluate the efficacy and safety of emergency variceal ligation for the prevention of rebleeding in cirrhotic patients who are found on initial endoscopy to have blood clots in the stomach but no actively bleeding esophageal and gastric varices or stigmata. METHODS: This study included 28 cirrhotic patients who underwent emergency prophylactic EVL and 41 who underwent an elective intervention between January 2009 and June 2014. Clinical outcomes were analyzed, including the rebleeding, 6-week mortality, and rebleeding-free survival rates. RESULTS: The rebleeding rate was higher in the emergency than in the elective group (28.6% vs. 7.3%, P=0.041). Multivariate analysis showed that emergency prophylactic EVL (odds ratio [OR] = 7.4, 95% confidence interval [CI]=1.634.8, P=0.012) and Child-Pugh score C (OR=10.6, 95% CI=1.4-80.8, P=0.022) were associated with rebleeding. In the emergency group, the gastric varices were associated with rebleeding (OR=12.0, 95% CI=1.7-83.5, P=0.012). CONCLUSIONS: Emergency EVL may be associated with variceal rebleeding when blood clots are present in the stomach without active esophageal and gastric variceal bleeding or stigmata. Elective intervention should be considered as a safer strategy for preventing variceal rebleeding in this situation.
Aged ; Emergency Medical Services ; Endoscopy, Digestive System ; Esophageal and Gastric Varices/complications/*diagnosis ; Female ; Gastrointestinal Hemorrhage/mortality/*prevention & control ; Humans ; Kaplan-Meier Estimate ; Liver Cirrhosis/complications/*diagnosis ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Recurrence ; Risk Factors ; Severity of Illness Index ; Stomach/pathology ; Survival Rate ; Thrombosis