Quantifiable changes in HBeAg expression predict therapeutic efficacy of peg-interferon alfa-2a in patients with HBeAg-positive chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate whether quantifiable changes in serum levels of hepatitis B e antigen (HBeAg) in response to 24 weeks of pegylated-interferon alfa-2a (Peg-IFN-a 2a) treatment are predictive of therapeutic efficacy at 48 weeks of treatment in HBeAg-positive chronic hepatitis B (CHB) patients and to investigate the efficacy of using an individualized antiviral treatment strategy.</p><p><b>METHODS</b>Ninety-six HBeAg-positive CHB patients with detectable HBeAg at week 24 of Peg-IFN-a 2a treatment were categorized according to the quantitative change in HBeAg (vs. pre-treatment baseline): group A, HBeAg decline more than 2 log; group B, HBeAg decline between 1 - 2 log; group C, HBeAg decline less than 1 log, which was then randomly divided into two sub-groups: C1 and C2. Group A, B, and C1 patients continued the original therapy for an additional 24 weeks, while group C2 patients were supplemented with lamivudine (3TC + Peg-IFN-a 2a) for the additional 24 weeks of treatment. All patients underwent liver biopsy at the end of treatment (week 48), and HBV covalently-closed circular (ccc)DNA was quantified as a measure of therapeutic efficacy. A, B, and C1 between-group multiple comparisons were made by the Nemenyi test; C1 and C2 between-group comparison was made by the Mann-Whitney U test. The significance of between-group differences in decreased HBV cccDNA vs. HBeAg/anti-HBe seroconversion was made by the Chi-squared test.</p><p><b>RESULTS</b>At week 48, the mean decrease of serum HBV cccDNA in each group was: A, 5.8 log10 copy/ml; B, 3.8 log10 copy/ml; C1, 2.8 log10 copy/ml; C2, 5.7 log10 copy/ml. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01); however, the difference between group B and C1 did not reach statistical significance (P = 0.19). The mean decrease of HBeAg in each group was: A, 2.7 log10 S/CO; B, 1.9 log10 S/CO; C1, 0.9 log10 S/CO; C2, 1.6 log10 S/CO. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The rate of patients who achieved undetectable HBV DNA in each group was: A, 87.5%; B, 34.5%; C1, 17.4%; C2, 85.0%. Statistically significant differences were observed for group A vs. B and C1 (P less than 0.01) and C1 vs. C2 (P less than 0.01). The HBeAg seroconversion rates were: A, 75.0%; B, 24.1%; C1, 13.0%; C2, 25.0%. Statistically significant differences were observed only for group A vs. B and C1 (P less than 0.01). Finally, group A achieved greater reduction in levels of cccDNA in liver tissues than B or C1 (P less than 0.01); however, the differences between B and C1 and between C1 and C2 did not reach statistical significance.</p><p><b>CONCLUSION</b>CHB patients who showed an HBeAg decline of more than 2 log at week 24 of Peg-IFN-a 2a treatment had better treatment outcome at week 48 than those who showed HBeAg decline less than 2 log at week 24. Augmenting the Peg-IFN-a 2a treatment with 3TC can improve the clinical response. A change of quantifiable HBeAg at week 24 of Peg-IFN-a 2a treatment may be a useful predictor of therapeutic efficacy of a 48-week antiviral regimen.</p>

Dynamics of hepatitis B virus covalently closed circular DNA after serum virology response / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To explore the dynamics of hepatitis B virus covalently closed circular DNA (cccDNA) and optimal duration of treatment after serum virology response.</p><p><b>METHODS</b>HBV cccDNA in liver biopsies and the serum HBV DNA were quantified by real time PCR, the serum makers were detected by enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>(1) The cccDNA in biopsy samples continued to decrease after serum virology responded. (2) The longer the treatment after serum virology response, the lower the cccDNA level in liver tissue. (3) Anti-HBe positive patients had lower cccDNA in liver tissue than anti-HBe negative patients. (4) cccDNA in liver tissue was undetectable in 12 out of the 18 case anti-HBe(+) patients. Serum virology response lasted 35 months and anti-HBe(+) lasted 30 months.</p><p><b>CONCLUSION</b>After serum virology responded, the longer the treatment, the lower the liver cccDNA. The cccDNA is undetectable in about 2/3 of the patients if the serum virological clearance lasts more than 35 months and anti-HBe lasts more than 30 months.</p>

Pathogenesis of liver fibrosis in patients with chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To explore the role of sinusoidal endothelial cell in the development of liver fibrosis, and to dissect the relationship among hepatic microcirculation disorders, hepatic sinusoidal capilarization and liver fibrosis.</p><p><b>METHODS</b>Liver biopsy was performed in fifty-six patients with chronic hepatitis B. The liver tissues were observed under light microscope and transmitted electronic microscope.</p><p><b>RESULTS</b>Of 56 cases, 39 cases were mild hepatitis, 10 were moderate hepatitis, and 7 were severe hepatitis. The morphology of hepatic stellate cells (HSCs) was similar to that of fibroblasts in the tissues of the patients with chronic hepatitis B. Collagenous fibers were deposited around the hepatic stellate cells. Electron-dense materials were deposited between sinusoidal endothelial cell and hepatic stellate cell. The size and amount of fenestraes of sinusoidal endothelial cells were reduced in 53 of 56 cases. The consecutive or inconsecutive membrane-like materials were observed along sinusoidal endothelial cells in 20 cases. Collagen fibers were observed in the space of Disse in 15 cases. Even in the patients with normal hepatic functions, red blood cells aggregation and microthrombi could be observed in the liver tissues.</p><p><b>CONCLUSION</b>Sinusoidal endothelial cells are involved in development of liver fibrosis by interacting with hepatic stellate cells. Hepatic microcirculation disorders and sinusoidal capillarization are important changes in the early stage of liver fibrosis.</p>

Effect of ursodeoxycholic acid on TGF beta1/Smad signaling pathway in rat hepatic stellate cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hepatic fibrosis is the key stage of the pathological progress from hepatic injury to cirrhosis. Ursodeoxycholic acid (UDCA) has been known as having significant clinical therapeutic effects on chronic liver diseases. Our research aimed to study the effect of UDCA on the signaling pathway of transforming growth factor beta1 (TGFbeta1)/Smad and discuss its possible molecular mechanisms of inhibiting hepatic fibrosis.</p><p><b>METHODS</b>Rat hepatic stellate cells were cultured in vitro and randomly assigned to 4 groups. Group A was control group, with only DMEM culture medium applied, and groups B, C, D were experimental groups, with different doses of UDCA (1.0 mmol/L, 0.5 mmol/L and 0.25 mmol/L respectively) added into their DMEM culture medium for further culture of 24 hours and 48 hours. The protein expressions of TGFbeta1, TGF type I receptor, Smad3, Smad4 and Smad7 were measured by Western blotting, as well as the expressions of TGFbeta1, Smad3, Smad7 and cAMP response element (CREB) binding protein (CBP) mRNA by real-time PCR. SPSS 11.5 statistical package was adopted for data analyses.</p><p><b>RESULTS</b>Compared with control group, the mRNA expressions of TGFbeta1 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly decreased (P < 0.05), the protein expressions of TGFbeta1 in the two above groups for 48 hours and in the high dose group for 24 hours significantly decreased (P < 0.05). The protein and mRNA expressions of Smad3 in each UDCA dose group for 24 hours and 48 hours significantly decreased, with significant difference among different UDCA dose groups and between that of 24 hours and 48 hours observed (P < 0.05). The protein and mRNA expressions of Smad7 in the high and middle UDCA dose groups for 24 hours and 48 hours significantly increased. The CBP mRNA expression in each UDCA dose group for 24 hours and 48 hours significantly decreased (P < 0.05), with significant difference among different UDCA dose groups observed (P < 0.05).</p><p><b>CONCLUSION</b>UDCA could curb the development of hepatic fibrosis through affecting the signaling pathway of TGFbeta1/Smad by inhibiting the expressions of TGFbeta1, Smad3 and CBP and increasing the expression of Smad7.</p>