This study aims to investigate the efficacy of forsythiaside A(FTA) against CCl_4-induced liver fibrosis and the mechanism. Specifically, activities of serum alanine/aspartate aminotransferase(ALT/AST) and hydroxyproline(HYP) level in liver were detected, and pathological morphology of liver was observed based on hematoxylin-eosin(HE) staining, Masson's trichrome staining, and Sirius red staining of liver. On this basis, the effect of FTA on liver fibrosis was evaluated. The mRNA expression of actin alpha 2/α-smooth muscle actin(Acta2/α-SMA), transforming growth factor β(Tgfβ), collagen Ⅰ alpha 1(Col1 a1), and collagen Ⅲ alpha 1(Col3 a1) in liver tissue and hepatic stellate cells(HSC) was determined by qPCR, and the protein expression of α-SMA in liver tissue and HSC was measured by Western blot to assess the inhibition of FTA on HSC activation. The protein expression of α-SMA, vi-mentin(Vim), vascular endothelial cadherin(Ve-cadherin), and platelet endothelial cell adhesion molecule-1(PECAM-1/CD31) was measured by Western blot to evaluate the reverse of endothelial-mesenchymal transition(EMT) by FTA. The efficacy of FTA in relieving CCl_4-induced liver fibrosis was evidenced by the alleviation of hepatocyte necrosis, liver inflammation, and hepatic collagen deposition. FTA decreased the mRNA expression of Acta2, Tgfβ, Col1 a1, and Col3 a1 and protein expression of α-SMA both in vivo and in vitro. FTA reversed the increase of α-SMA and Vim and the decrease of CD31 and Ve-cadherin in livers from mice treated with CCl_4. Therefore, FTA alleviated CCl_4-induced liver fibrosis in mice via suppressing HSC activation and reversing EMT.
Animals ; Mice ; Actins/metabolism* ; Alanine Transaminase/blood* ; Carbon Tetrachloride/metabolism* ; Collagen/metabolism* ; Hepatic Stellate Cells ; Liver/drug effects* ; Liver Cirrhosis/genetics* ; RNA, Messenger/metabolism* ; Transforming Growth Factor beta/metabolism* ; Glycosides/therapeutic use*

Objective: To investigate the effects of plasma lipopolysaccharide (LPS) concentration changes on platelet release of vascular endothelial growth factor (VEGF) and thrombospondin (TSP)-1 in patients with decompensated cirrhotic portal hypertension after transjugular intrahepatic portosystemic shunt (TIPS) procedure. Methods: 169 cases with cirrhotic portal hypertension were enrolled, of which 81 cases received TIPS treatment. LPS, VEGF, and TSP-1 concentrations with different Child-Pugh class in peripheral blood plasma of patients were measured. After pre-incubation of normal human platelets with different concentrations of LPS and stimulated by collagen in vitro, platelet PAC-1 expression rate, VEGF, and TSP-1 concentrations were detected. PAC-1 expression rate and the concentrations of LPS, VEGF and TSP-1 in peripheral blood plasma of patients before and after TIPS procedure were detected. The relationship between plasma LPS, VEGF and TSP-1 concentrations and Child-Pugh score changes in patients after TIPS procedure was analyzed. Statistical analysis was performed by t-test, one-way ANOVA or Pearson's rho according to different data. Results: Plasma LPS and TSP-1 concentrations were significantly higher in Child-Pugh class C patients than class A and B, but the concentration of plasma VEGF was significantly lower than class A and B (P < 0.01). In vitro experiments showed that concentration of LPS, TSP-1, and platelet PAC-1 expression rate was higher in the supernatant, but the difference in the concentration of VEGF in the supernatant was not statistically significant. Portal vein pressure and platelet activation were significantly decreased (P < 0.01) in patients after TIPS procedure. Portal venous pressure, platelet activation, plasma LPS, and TSP-1 levels were significantly decreased continuously, while VEGF levels were significantly increased continuously after TIPS procedure. Plasma LPS concentration was positively correlated with TSP-1 concentration (r = 0.506, P < 0.001), and negatively correlated with VEGF concentration (r = -0.167, P = 0.010). Child-Pugh score change range was negatively correlated with change range of plasma VEGF concentration (r = -0.297, P = 0.016), and positively correlated with change range of plasma TSP-1 concentration (r = 0.145, P = 0.031) after TIPS. Conclusion: Portal venous pressure gradient, plasma LPS concentration and corresponding platelet activation was decreased in cirrhotic portal hypertension after TIPS procedure, and with TSP-1 reduction and VEGF elevation it is possible to reduce the liver function injury caused by portal venous shunt.
Blood Platelets ; Humans ; Hypertension, Portal/etiology* ; Lipopolysaccharides ; Liver Cirrhosis/complications* ; Plasma ; Portasystemic Shunt, Transjugular Intrahepatic/adverse effects* ; Vascular Endothelial Growth Factor A

Objective: Autologous peripheral blood stem cells (PBSC) derived from bone marrow can promote liver regeneration and improve the liver function of patients, but there are few studies on its effect on the long-term outcomes in patients with decompensated cirrhosis. Based on previous work, this study observed the clinical outcomes of PBSC treatment in patients with decompensated cirrhosis for 10 years, in order to provide more data support for the safety and efficacy of stem cells in clinical applications. Methods: Data of patients with decompensated liver cirrhosis who completed PBSC treatment in the Department of Gastroenterology of the First Affiliated Hospital of Air Force Military Medical University from August 2005 to February 2012 were included. The follow-up endpoint was death or liver transplantation, and patients who did not reach the follow-up endpoint were followed-up for at least 10 years. The patients with decompensated liver cirrhosis who met the conditions for PBSC treatment but did not receive PBSC treatment in our hospital during the same period were used as controls. Results: A total of 287 cases with decompensated liver cirrhosis had completed PBSC treatment, and 90 cases were lost to follow-up within 10 years after surgery. A total of 151 cases with complete survival follow-up data were included in the control group. There were no statistically significant differences in baseline information such as gender, age, etiological composition and liver function score between the two groups. The 10-year survival rate was higher in PBSC than control group (37.56% vs. 26.49%, P<0.05). Cholinesterase, albumin, international normalized ratio, Child-Turcotte-Pugh score, model for end-stage liver disease score, and other indicators were gradually recovered within 3 months to 1 year after PBSC treatment, and stabilized at a more desirable level in the long-term after follow-up for up to 10 years. There was no statistically significant difference in the incidence of liver cancer between the two groups (25.22% vs.31.85%, P=0.267). The age of onset of hepatocellular carcinoma was later in PBSC than control group [(56.66±7.21) years vs. (52.69±8.42) years, P<0.05]. Conclusions: This long-term observational follow-up study of more than ten years confirms that PBSC treatment can bring long-term benefits to patients with decompensated cirrhosis, with good long-term safety, thus providing more data support on the safety and efficacy of stem cells for clinical applications.
End Stage Liver Disease ; Follow-Up Studies ; Humans ; Liver Cirrhosis/drug therapy* ; Middle Aged ; Peripheral Blood Stem Cells ; Severity of Illness Index ; Treatment Outcome

OBJECTIVE: To explore the diagnostic value of the serum metabolites identified by high-performance liquid chromatography-mass spectrometry (HPLC/MS) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: A total of 126 patients admitted to Tianjin Third Central Hospital were enrolled, including 27 patients with HBV-related hepatitis with negative viral DNA (DNA-N), 24 with HBV-related hepatitis with positive viral DNA, 24 with HBV-related liver cirrhosis, 27 with HBV-related HCC undergoing surgeries or radiofrequency ablation, and 24 with HBV-related HCC receiving interventional therapy, with 25 healthy volunteers as the normal control group. Serum samples were collected from all the subjects for HPLC/MS analysis, and the data were pretreated to establish an orthogonal partial least- squares discriminant analysis (OPLS-DA) model. The differential serum metabolites were preliminarily screened by comparisons between the HBV groups and the control group, and the characteristic metabolites were identified according to the results of non-parametric test. The potential clinical values of these characteristic metabolites were evaluated using receiver operator characteristic curve (ROC) analysis. RESULTS: A total of 25 characteristic metabolites were identified in the HBV- infected patients, including 9 lysophosphatidylcholines, 2 fatty acids, 17α-estradiol, sphinganine, 5-methylcytidine, vitamin K2, lysophosphatidic acid, glycocholic acid and 8 metabolites with few reports. The patients with HBV- related HCC showed 22 differential serum metabolites compared with the control group, 4 differential metabolites compared with patients with HBV-related liver cirrhosis; 10 differential metabolites were identified in patients with HBV-related HCC receiving interventional therapy compared with those receiving surgical resection or radiofrequency ablation. From the normal control group to HBV-related HCC treated by interventional therapy, many metabolites underwent variations following a similar pattern. CONCLUSIONS We identified 25 characteristic metabolites in patients with HBV-related HCC, and these metabolites may have potential clinical values in the diagnosis of HBV-related HCC. The continuous change of some of these metabolites may indicate the possibility of tumorigenesis, and some may also have indications for the choice of surgical approach.
Carcinoma, Hepatocellular ; blood ; diagnosis ; virology ; Case-Control Studies ; Chromatography, High Pressure Liquid ; DNA, Viral ; blood ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; blood ; virology ; Humans ; Liver Cirrhosis ; virology ; Liver Neoplasms ; blood ; diagnosis ; virology ; Mass Spectrometry ; Metabolome ; Metabolomics ; ROC Curve

OBJECTIVE: This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. METHODS: Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 μL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. RESULTS: CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. CONCLUSION These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.
Animals ; Blood Chemical Analysis ; Carbon Tetrachloride ; toxicity ; Hepcidins ; pharmacology ; Injections, Intraperitoneal ; Interleukin-6 ; pharmacology ; Iron ; blood ; metabolism ; Leukocytosis ; chemically induced ; therapy ; Liver Cirrhosis ; chemically induced ; therapy ; Male ; Rats ; Thioacetamide ; toxicity ; Thrombocytopenia ; chemically induced ; therapy ; Transferrin ; metabolism

OBJECTIVE: The most common cause of hemorrhage after paracentesis is direct needle puncture of the inferior epigastric artery (IEA). This study examined the relationship between the amount of the ascites and the location of the IEA in liver cirrhosis. METHODS: Abdominal computed tomography (CT) examinations of patients with liver cirrhosis were reviewed retrospectively and divided into two groups according to the amount of ascites. The distances between the midline and the IEAs of both sides were measured at the umbilicus, McBurney's point, anterior superior iliac spine, and mid-inguinal level. Branching of the IEAs, abdominal wall and mesenteric varices in the abdomen below the umbilicus level were recorded. RESULTS: A total of 120 abdominal CTs were reviewed. The distances from the midline to the IEA in the large ascites group were longer than those in the small ascites group at the level of the right McBurney's point (44.5±14.6 mm vs. 39.6±11.8 mm, P=0.043) and left McBurney's point (48.6±15.3 mm vs. 43.3±11.5 mm, P=0.035). The incidence of abdominal wall varices was higher in the large ascites group (21.7% vs. 5.0%, P=0.014). CONCLUSION: In patients with liver cirrhosis, the large amount of ascites might be associated with lateralizing the location of the IEA. Moreover, it may be necessary to confirm the blood vessels in the abdominal wall and mesentery near the puncture site by bedside ultrasound before the paracentesis.
Abdomen ; Abdominal Wall ; Ascites ; Blood Vessels ; Epigastric Arteries ; Hemoperitoneum ; Hemorrhage ; Humans ; Incidence ; Liver Cirrhosis ; Liver ; Mesentery ; Needles ; Paracentesis ; Punctures ; Retrospective Studies ; Spine ; Tomography, X-Ray Computed ; Ultrasonography ; Umbilicus ; Varicose Veins

BACKGROUND: Liver fibrosis evaluation is an important issue in chronic liver disease patients. We aimed to develop noninvasive liver fibrosis biomarkers based on transient elastography (TE, FibroScan®) through retrospective review of clinicopathological data. METHODS: We recruited 278 chronic hepatitis B patients who underwent Fibroscan and HBV DNA testing. A total of 115 HBeAg-positive and 159 HBeAg-negative chronic hepatitis B patients were analyzed. A total of 100 hepatitis C patients were analyzed. Successful fibroscan data, gamma-glutamyl transferase (GGT) to platelet ratio (GPR), platelet count, AST, ALT, international normalized ratio of prothrombin time, total cholesterol, triglycerides, bilirubin, mean platelet volume, AST to platelet ratio index, fibrosis index based on four factors (FIB-4), neutrophil to lymphocyte ratio (NLR), and NLR to platelet ratio were analyzed to determine the new noninvasive markers for assessing liver fibrosis. RESULTS: Elevated GPR (OR=9.1, P=0.011) and FIB-4 (OR=2.3, P=0.01) were associated with greater risk of liver fibrosis in chronic hepatitis B patients. FIB-4 (OR=6.04, P=0.005) was a risk factor for liver fibrosis in HBeAg-positive patients. FIB-4 (OR=2.371, P=0.015) and GPR (OR=33.78, P=0.003) were liver fibrosis risk factor in HBeAg-negative patients. In chronic hepatitis C patients, GGT (OR=1.033, P=0.002), triglyceride (OR=−0.990, P=0.038) and FIB-4 (OR=3.499, P=0.006) showed statistical significances. The AUCs were 0.816 in FIB-4 (P<0.001) and 0.849 in GPR (P<0.001). CONCLUSIONS: FIB-4 and GPR may be useful blood markers for assessing liver fibrosis in chronic hepatitis B and hepatitis C patients. Further well-designed prospective study is required to validate these noninvasive blood markers in clinical practice.
Area Under Curve ; Bilirubin ; Biomarkers ; Blood Platelets ; Cholesterol ; DNA ; Elasticity Imaging Techniques ; Fibrosis ; Hepatitis B ; Hepatitis B, Chronic ; Hepatitis C ; Hepatitis C, Chronic ; Hepatitis ; Hepatitis, Chronic ; Humans ; International Normalized Ratio ; Liver Cirrhosis ; Liver Diseases ; Liver ; Lymphocytes ; Mean Platelet Volume ; Neutrophils ; Platelet Count ; Prospective Studies ; Prothrombin Time ; Retrospective Studies ; Risk Factors ; Transferases ; Triglycerides

BACKGROUND/AIMS: An estimated 80 million people worldwide are infected with viremic hepatitis C virus (HCV). Even after eradication of HCV with direct acting antivirals (DAAs), hepatic fibrosis remains a risk factor for hepatocarcinogenesis. Recently, we confirmed the applicability of microfibrillar-associated protein 4 (MFAP4) as a serum biomarker for the assessment of hepatic fibrosis. The aim of the present study was to assess the usefulness of MFAP4 as a biomarker of liver fibrosis after HCV eliminating therapy with DAAs. METHODS: MFAP4 was measured using an immunoassay in 50 hepatitis C patients at baseline (BL), the end-of-therapy (EoT), and the 12-week follow-up (FU) visit. Changes in MFAP4 from BL to FU and their association with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelets, the AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4), and albumin were analyzed. RESULTS: MFAP4 serum levels were representative of the severity of hepatic fibrosis at BL and correlated well with laboratory parameters, especially APRI (Spearman correlation, R²=0.80). Laboratory parameters decreased significantly from BL to EoT. MFAP4 serum levels were found to decrease from BL and EoT to FU with high statistical significance (Wilcoxon p<0.001 for both). CONCLUSIONS: Our findings indicate that viral eradication resulted in reduced MFAP4 serum levels, presumably representing a decrease in hepatic fibrogenesis or fibrosis. Hence, MFAP4 may be a useful tool for risk assessment in hepatitis C patients with advanced fibrosis after eradication of the virus.
Alanine Transaminase ; Antiviral Agents ; Aspartate Aminotransferases ; Biomarkers ; Blood Platelets ; Extracellular Matrix Proteins ; Fibrosis ; Follow-Up Studies ; Hepacivirus ; Hepatitis C ; Hepatitis C, Chronic ; Hepatitis ; Humans ; Immunoassay ; Liver Cirrhosis ; Risk Assessment ; Risk Factors

The coagulation profile of patients with end-stage liver disease (ESLD) is different from that of healthy individuals. Because hemostasis is rebalanced in chronic liver disease, prophylactic transfusion of blood products may be not necessary for these patients even if they show severe coagulation dysfunction in conventional coagulation results. A 44-year-old man with hepatocellular carcinoma, cholangiocarcinoma and liver cirrhosis was scheduled for extra-hepatic mass excision under general anesthesia. His preoperative tests showed severe thrombocytopenia 19 × 10⁹/L. The patient underwent extrahepatic mass excision surgery under general anesthesia without transfusion of blood products. The post-operative course was uneventful without requiring any further hemostatic therapy. In this case report, we focus on the concept of rebalanced hemostasis in ESLD, and coagulation management based on rotational thromboelastometry.
Adult ; Anesthesia, General ; Blood Coagulation ; Blood Platelets* ; Carcinoma, Hepatocellular ; Cholangiocarcinoma ; Hemostasis* ; Humans ; Liver Cirrhosis ; Liver Diseases* ; Liver* ; Platelet Count* ; Thrombelastography ; Thrombocytopenia

OBJECTIVES: The objective of this study was to assess the relationship between systolic and diastolic blood pressure (SBP, DBP) and the risk of death from specific causes other than cardiovascular diseases. METHODS: We calculated the risk of specific death by SBP and DBP categories for 506 508 health examinees in 2002-2003 using hazard ratios (HRs) and 95% confidence intervals (CIs) in a Cox proportional hazards model. RESULTS: Compared to normal levels (SBP < 120 or DBP < 90 mmHg), stage I systolic and diastolic hypertension (SBP 140-159, DBP 85- 89 mmHg, respectively) were associated with an increased risk of death from diabetes mellitus, alcoholic liver disease, and renal failure (HR, 1.83; 95% CI, 1.51 to 2.22; HR, 1.24; 95% CI, 1.06 to 1.46; HR, 2.30; 95% CI, 1.64 to 3.21; HR, 1.67; 95% CI, 1.27 to 2.20; HR, 1.99; 95% CI, 1.41 to 2.81; HR, 1.31; 95% CI, 0.99 to 1.73, respectively), but a decreased risk of death from intestinal pneumonia (HR, 0.64; 95% CI, 0.42 to 0.98; HR, 0.59; 95% CI, 0.39 to 0.91). Only stage II systolic hypertension (SBP ≥160 mmHg) was associated with an increased risk of death from pneumonia, liver cirrhosis, and intestinal ischemia (HR, 1.54; 95% CI, 1.19 to 1.98; HR, 1.46; 95% CI, 1.00 to 2.15; HR, 3.77; 95% CI, 1.24 to 11.40, respectively), and stage I and II diastolic hypertension (SBP 140-159 and ≥160 mmHg) were associated with an increased risk of death from intestinal ischemia (HR, 3.07; 95% CI, 1.27 to 7.38; HR, 4.39; 95% CI, 1.62 to 11.88, respectively). CONCLUSIONS: An increase in blood pressure levels may alter the risk of death from certain causes other than cardiovascular diseases, a well-known outcome of hypertension, although the mechanism of these associations is not well documented.
Adult* ; Blood Pressure* ; Cardiovascular Diseases ; Cohort Studies* ; Diabetes Mellitus ; Humans ; Hypertension ; Ischemia ; Liver Cirrhosis ; Liver Diseases, Alcoholic ; Pneumonia ; Proportional Hazards Models ; Renal Insufficiency