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1.  What MELD score mandates use of entecavir for ACLF-HBV HBeAg-negative patients? 
AIM: To investigate optimal timing for therapeutic efficacy of entecavir for acute-on-chronic hepatitis B liver failure (ACLF-HBV) in hepatitis B e antigen (HBeAg)-negative patients.
METHODS: A total of 109 inpatients with ACLF-HBV were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital, Sun Yat-sen University from October 2007 to October 2010. Entecavir 0.5 mg/d was added to each patient’s comprehensive therapeutic regimen. Patients were divided into three groups according to model for end-stage liver disease (MELD) score: high (≥ 30, 20 males and 4 females, mean age 47.8 ± 13.5 years); intermediate (22-30, 49 males and 5 females, 45.9 ± 12.4 years); and low (≤ 22, 28 males and 3 females, 43.4 ± 9.4 years). Statistical analysis were performed using SPSS 11.0 software. Data with normal distribution were expressed as mean ± SD and comparisons were made with Student’s t tests. A value of P < 0.05 was considered statistically significant. Viral loads were related exponentially and logarithmic data were used for analysis.
RESULTS: For 24 patients with MELD score ≥ 30, treatment lasted 17.2 ± 16.5 d. Scores before and after treatment were significantly different (35.97 ± 4.87 and 40.48 ± 8.17, respectively, t = -2.762, P = 0.011); HBV DNA load was reduced (4.882 ± 1.847 copies log10/mL to 3.685 ± 1.436 copies log10/mL); and mortality rate was 95.83% (23/24). Of 54 patients with scores of 22-30, treatment lasted for 54.0 ± 43.2 d; scores before and after treatment were 25.87 ± 2.33 and 25.82 ± 13.92, respectively (t = -0.030, P = 0.976); HBV DNA load decreased from 6.308 ± 1.607 to 3.473 ± 2.097 copies log10/mL; and mortality was 51.85% (28/54). Of 31 patients with scores ≤ 22, treatment lasted for 66.1 ± 41.9 d; scores before and after treatment were 18.88 ± 2.44 and 12.39 ± 7.80, respectively, (t = 4.860, P = 0.000); HBV DNA load decreased from 5.841 ± 1.734 to 2.657 ± 1.154 copies log10/mL; and mortality was 3.23% (1/31).
CONCLUSION: For HBeAg-negative patients with ACLF-HBV, when entecavir was added to comprehensive therapy, a MELD score ≥ 30 predicted very poor prognosis due to fatal liver failure.
PMCID: PMC3435788  PMID: 22969236
Acute-on-chronic hepatitis B liver failure; Hepatitis B e antigen negativity; Entecavir; Model for end-stage liver disease; Mortality
2.  Effect of healthcare insurance policy on the quality of life of chronic hepatitis C patients receiving interferon α-2a plus ribavirin therapy 
The aim of this study was to evaluate the effect of pegylated interferon α-2a plus ribavirin therapy on the quality of life (QOL) of chronic hepatitis C patients when this treatment was paid for by healthcare insurance. The QOL questionnaire (GQOLI-74) was used to assess patient QOL. A total of 42 cases received 1-year pegylated interferon α-2a plus ribavirin treatment paid for by Guangzhou Medical Insurance (group A), and 30 cases received treatment self-subsidized by the patients themselves (group B). Another 30 patients did not receive interferon therapy (group C). All groups completed the evaluation twice; prior to interferon treatment (T0) and at the end of treatment (T1). There was no statistically significant difference among the three groups (P>0.05). At T1, patients in group A had higher scores for each questionnaire dimension and a higher total score than those of group C (P<0.05). Patients in group B also had higher scores than those of group C (P<0.05), except for material well-being (P=0.305). Compared with group B, patients in group A had higher scores for mental function, material well-being and a higher total score (P<0.05). Patients in group A had higher scores for each dimension and a higher total score at T1 than at T0 (P=0.05), while patients in group B had higher scores for physical function, social function and a higher total score at T1 than at T0 (P=0.05). Pegylated interferon α-2a plus ribavirin treatment is able to improve the QOL of chronic hepatitis C patients. Patients whose treatment was financed by medical insurance exhibited increased improvement in QOL compared to those who paid for their own treatment.
PMCID: PMC3438712  PMID: 22970017
chronic hepatitis C; medical insurance; pegylated-interferon α-2a; quality of life
3.  Venous diethylene glycol poisoning in patients with preexisting severe liver disease in China 
AIM: To analyze the clinical presentation of venous diethylene glycol (DEG) poisoning in patients with preexisting severe liver disease and factors that correlate with DEG poisoning.
METHODS: Retrospective chart review was performed to analyze the epidemiology, clinical presentation, hepatorenal functions, hemodynamics and pathological characteristics of 64 patients with severe liver disease who received intravenous armillarisin-A, the solvent of which was DEG. Comparative analyses of correlating factors and causes for poisoning were based on the presence or absence of poisoning.
RESULTS: Of the 64 patients who received armillarisin-A, 15 were found to have DEG poisoning. Twelve poisoned patients died. After a mean of 5 d, the poisoned patients displayed acute renal failure. Metabolic acidosis occurred in 13 cases. BUN, Cr, and CO2 values were significantly elevated and exacerbation of digestive tract symptoms and/or symptom was noted in 11 cases. Neurological system impairment was observed in 10 cases after 2 wk. Compared to the 49 non-poisoned patients, the poisoned patients exhibited significantly lower RBC and Hb values and higher WBC count. Renal biopsy from the poisoned patients revealed acute tubular necrosis and interstitial nephritis. Significant differences in preexisting severe hepatitis, ascites, renal disease, and diuretic therapy were found between groups. Prior to diethylene glycol injections, the mean values for neutral granular cells, BUN, Cr, calcium and phosphorous ions differed significantly between groups.
CONCLUSION: Venous diethylene glycol poisoning is characterized by oliguric acute renal failure, metabolic acidosis, digestive symptoms, nervous system impairment, and a high probability of anemia and WBC proliferation. Mortality is high. Correlative factors include preexisting severe liver disease, renal disease, and infection.
PMCID: PMC2712859  PMID: 18506932
Diethylene glycol; Poisoning; Liver disease; Clinical feature
4.  Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance 
AIM: To study the expression of suppressor of cytokine signaling-1 (SOCS-1) in the liver tissues of chronic hepatitis B (CHB) and the clinical significance of this expression.
METHODS: The expression of SOCS-1 in liver tissues of 45 cases of CHB was investigated by immunohistochemical staining, and its correlations with inflammation grades and fibrosis stage were analyzed by SPSS statistics software.
RESULTS: The result showed SOCS-1 expressing could be observed in the liver tissue of CHB. The expression of SOCS-1 was mainly distributed near the portal area in the liver tissue of mild inflammation CHB group, and was diffusely distributed in the liver tissue of moderate and severe inflammation groups. SOCS-1 positive stains mainly appear in the hepatocytes, only a few of liver interstitial cells were involved. Inside the hepatocyte, SOCS-1 positive stains are mainly distributed in the plasma. Some of the staining was observed on the membrane. The inclusion bodies in the plasma of hepatocytes were observed occasionally. There were both obvious correlations between the expression of SOCS-1 and the inflammatory grade, and that between the expression of SOCS-1 and the fibrosis stage.
CONCLUSION: The distribution of SOCS-1 in the liver tissue of CHB is variable. This expression was correlated with the inflammation grade and fibrosis stage.
PMCID: PMC2681154  PMID: 18203295
Suppressor of cytokine signaling-1; Janus kinase-signal transducer and activator of transcription; Chronic hepatitis B; Inflammation; Fibrosis
5.  Expansion of myeloid-derived suppressor cells from peripheral blood decreases after 4-week antiviral treatment in patients with chronic hepatitis C 
Myeloid-derived suppressor cells (MDSCs) are one of the most important regulators of anti-tumor T-cell responses in cancers. This study aimed to investigate MDSCs in the peripheral blood of patients with chronic hepatitis C (CHC) before and after 4-week treatment with pegylated interferon (PEG-IFN) and ribavirin, and to evaluate their correlation with CD4+CD25high regulatory T cells (Tregs) and clinical parameters. A total of 80 patients with CHC were enrolled into this study, 37 of whom were treated with PEG-IFN and ribavirin. Compared with healthy controls (0.462% [range 0.257%-0.634%]), the proportion of MDSCs in the peripheral blood of 80 CHC patients (0.601% [range 0.333%-1.027%]) increased significantly before therapy (P=0.011). For 37 HCV patients, the proportion of circulating MDSCs (0 w: 0.597% [range 0.296%-1.021%], 4 w: 0.126% [0.066%-0.239%], P<0.01) and Tregs (0 w: 2.467±0.927%, 4 w: 2.074±0.840%, P=0.047) decreased significantly after 4-week antiviral treatment. No significant correlation was found between MDSCs and Tregs. These findings suggest that MDSCs expand in the peripheral blood of CHC patients, but decrease after 4-week antiviral treatment.
PMCID: PMC4057852  PMID: 24955173
Myeloid-derived suppressor cells; hepatitis virus C; interferon; regulatory T cells; immunosuppression
6.  Serum proteomics analysis and comparisons using iTRAQ in the progression of hepatitis B 
The aim of this study was to analyze the changes in serum protein levels in the progression of hepatitis B using isobaric tags for relative and absolute quantitation (iTRAQ) analysis, in addition to comparing the serum protein levels of patients with chronic hepatitis B (CHB), patients with hepatitis B virus-induced acute-on-chronic liver failure (HBV-induced ACLF) and normal individuals. Protein analysis was performed on 15 serum samples using iTRAQ. The study population included healthy controls (n=5), patients with CHB (n=5) and patients with HBV-induced ACLF (n=5). Western blotting was used to verify the results in an additional nine serum samples from healthy controls, patients with CHB and patients with HBV-induced ACLF (n=3, respectively). Using iTRAQ analysis, 16 different serum proteins with ≥1.5-fold differences in expression levels were identified in the patients with CHB and ACLF compared with the healthy controls. Five of those proteins, C-reactive protein precursor, hemoglobin β chain variant Hb S-Wake, apolipoprotein J precursor, platelet factor 4 precursor and vitronectin, which demonstrated the greatest differences in their expression levels and the most significant correlation with liver diseases, were subsequently verified using western blotting. The western blotting results were consistent with the results from the iTRAQ. Two of the five proteins are not classified by biological process, and the biological functions of all the proteins in HBV-induced ACLF remain unclear. This preliminary study demonstrated that a correlation between the expression of various serum proteins and the different pathogenetic conditions induced by HBV may exist. The analysis of a larger number of samples is required to identify potential protein biomarkers that may be involved in the pathogenesis and progression of hepatitis B.
PMCID: PMC3820766  PMID: 24223640
serum; proteomics; isobaric tags for relative and absolute quantitation; hepatitis B
7.  Dynamic Changes of Clinical Features that Predict the Prognosis of Acute-on-Chronic Hepatitis B Liver Failure: A Retrospective Cohort Study 
Objective: The natural history of acute-on-chronic hepatitis B liver failure (ACHBLF) is complex and highly variable. However, the global clinical characteristics of this entity remain ill-defined. We aimed to investigate the dynamic patterns of the natural progression as well as their impact on the outcomes of ACHBLF. Methods: The clinical features and disease states were retrospectively investigated in 54 patients with ACHBLF at the China South Hepatology Center. The clinical and laboratory profiles including hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and spontaneous bacterial peritonitis (SBP) were evaluated. The disease state estimated by the model for end-stage liver disease (MELD) score and the dynamic patterns during the clinical course of ACHBLF were extrapolated. Results: Twenty-two patients died during the 3-month follow-up period (40.74%). The patients were predominantly male (88.89%). Baseline characteristics showed that there were significant differences in only hepatitis B virus (HBV) DNA levels and platelet count between the deceased and surviving patients (P=0.014 and P=0.012, respectively). Other baseline characteristics were similar in both groups. The dynamic state of the MELD score gradually increased from an initial hepatic flare until week 4 of ACHBLF progression. There were notable changes of the dynamic state of the MELD score at two time points (week 2 and week 4) during ACHBLF progression. The MELD scores were significantly greater in the death group (24.80±2.99) than in the survival group (19.49±1.96, P<0.05) during the clinical course of ACHBLF; the MELD scores of the survival group began to decrease from week 4, while they continued to rise and eventually decreased as more patients died. The gradients of the ascent and descent stages could predict exactly the severity and prognosis of ACHBLF. Conclusions: The natural progression of ACHBLF could be divided approximately into four stages including ascent, plateau, descent, and convalescence stages according to different trends of liver failure progression, respectively. Thus, the special patterns of the natural progression of ACHBLF may be regarded as a significant predictor of the 3-month mortality of ACHBLF.
PMCID: PMC3804791  PMID: 24151437
Dynamic patterns; Prognosis; Acute-on-chronic hepatitis B liver failure; Clinical features; and MELD score.
8.  Liver myofibroblasts regulate the phenotype and function of monocytes through soluble factors in cirrhosis 
The ability of lymphocytes and macrophage-derived cytokines and chemokines to modulate the activation of stromal cells during immune responses is well-documented, but few studies have investigated whether liver myofibroblasts shape the phenotype and function of monocytes in liver disease. In the present study, Kupffer cells were demonstrated to be activated in the inflamed livers of patients with cirrhosis and be in close contact with liver myofibroblasts. The Kupffer cells from cirrhotic livers expressed significantly elevated levels of PD-L1 (also termed B7-H1), TLR4, CD80, CD32 and CD64 relative to those from normal livers. Consistent with this finding, the expression of these surface molecules was significantly upregulated in monocytes following exposure to liver myofibroblasts originating from inflamed livers. Accordingly, the liver myofibroblast-exposed monocytes exhibited a significant increase in dextran endocytosis. These data reveal that bidirectional interactions between liver myofibroblasts and Kupffer cells may function as an ‘amplification loop’ to enhance inflammation further in the liver. Liver myofibroblasts are central in the pathogenesis of liver diseases and should be considered as targets for the rational design of effective immune-based anti-inflammation therapies. Furthermore, it was also demonstrated that skin fibroblasts were as effective as liver myofibroblasts at inducing monocyte activation, suggesting that fibroblasts, which are numerous in the body, may represent an underrated cell population that is actively involved in immunomodulatory functions.
PMCID: PMC3523956  PMID: 23251256
Kupffer cell; monocyte activation; liver cirrhosis; liver myofibroblasts; liver immunology
9.  Effect of Revaccination Using Different Schemes among Adults with Low or Undetectable Anti-HBs Titers after Hepatitis B Virus Vaccination▿  
Clinical and Vaccine Immunology : CVI  2010;17(10):1548-1551.
Our objective was to investigate the effect of various reimmunization schemes for hepatitis B in adults with low or undetectable anti-HBs titers. Over 2 years, 10 μg of Saccharomyces cerevisiae-recombinant hepatitis B virus (HBV) vaccine (synthesized in China) was used in at least one standardized scheme to immunize 2,310 healthy male and nonpregnant female adults. Of these, 240 subjects tested negative for hepatitis B markers. These 240 subjects were equally divided into 4 groups. The first group, designated Engerix-40, was revaccinated with 40 μg Engerix-B; the second, Engerix-20, was revaccinated with 20 μg Engerix-B; the third, Chinese-20, was revaccinated with 20 μg Chinese-made yeast-recombinant vaccine; and the last group, Chinese-10, was revaccinated with 10 μg Chinese-made yeast-recombinant vaccine. Blood samples were collected before and 1, 2, 8, and 12 months after the first injection. The anti-HBs-positive conversion rates of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than that of the Chinese-10 group (P < 0.01). Over time, the anti-HBs conversion rate increased in all groups, but values were significantly different from those for the other groups only in the Chinese-10 group (P < 0.001). The anti-HBs geometric mean titers (GMTs) of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than in the Chinese-10 group (P < 0.05). Increased doses raise and maintain anti-HBs titers in subjects with low or undetectable titers after HBV vaccination.
PMCID: PMC2952995  PMID: 20719983
10.  HGF and Direct Mesenchymal Stem Cells Contact Synergize to Inhibit Hepatic Stellate Cells Activation through TLR4/NF-kB Pathway 
PLoS ONE  2012;7(8):e43408.
Bone marrow-derived mesenchymal stem cells (BMSCs) can reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs.
We used BMSCs directly and indirectly co-culture system with HSCs to evaluate the anti-fibrosis effect of BMSCs. Cell proliferation and activation were examined in the presence of BMSCs and HGF. c-met was knockdown in HSCs to evaluate the effect of HGF secreted by BMSCs. The TLR4 and Myeloid differentiation primary response gene 88(MyD88) mRNA levels and the NF-kB pathway activation were determined by real-time PCR and western blotting analyses. The effect of BMSCs on HSCs activation was investigated in vitro in either MyD88 silencing or overexpression in HSCs. Liver fibrosis in rats fed CCl4 with and without BMSCs supplementation was compared. Histopathological examinations and serum biochemical tests were compared between the two groups.
BMSCs remarkably inhibited the proliferation and activation of HSCs by interfering with LPS-TLR4 pathway through a cell–cell contact mode that was partially mediated by HGF secretion. The NF-kB pathway is involved in HSCs activation inhibition by BMSCs. MyD88 over expression reduced the BMSC inhibition of NF-kB luciferase activation. BMSCs protected liver fibrosis in vivo.
BMSCs modulate HSCs in vitro via TLR4/MyD88/NF-kB signaling pathway through cell–cell contact and secreting HGF. BMSCs have therapeutic effects on cirrhosis rats. Our results provide new insights into the treatment of hepatic fibrosis with BMSCs.
PMCID: PMC3426540  PMID: 22927965
11.  Upregulator of Cell Proliferation Predicts Poor Prognosis in Hepatocellular Carcinoma and Contributes to Hepatocarcinogenesis by Downregulating FOXO3a 
PLoS ONE  2012;7(7):e40607.
The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis.
URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin-embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non-cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a.
IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27Kip1 and p21Cip1 and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity.
URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease.
PMCID: PMC3398045  PMID: 22815774

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