Yen-Cheng Chiu

Clinical significance of serum HBsAg levels and association with liver histology in HBeAg positive chronic hepatitis B.

BACKGROUND Despite its recognized role as a prognostic marker for antiviral treatment, the clinical significance of serum hepatitis B surface antigen (HBsAg) level in the immune-clearance stage of chronic hepatitis B remains unclear. OBJECTIVES To characterize how HBsAg level and various clinical and virological factors are related and analyze the correlation of HBsAg with liver histology. STUDY DESIGN A total of 198 treatment-naïve HBeAg-positive chronic hepatitis B patients were enrolled. Serum HBV DNA and HBsAg were determined quantitatively. Mutations of precore or basal core promoter (BCP) were also determined. Finally, liver necroinflammation grading and fibrosis stage were evaluated by Knodell score and Ishak score, respectively. RESULTS Lower HBsAg levels were found in patients with genotype C HBV infection, or in the presence of precore or mutations, or Knodell necroinflammation grading ≥ 7, or advanced fibrosis (Ishak stage 4-6). HBsAg level displayed a strong correlation with HBV DNA (r = 0.727, P < 0.001) and also exhibited a positive correlation with intrahepatic HBcAg expression in either cytoplasm (r = 0.420, P < 0.001) or nucleus (r = 0.401, P < 0.001). Examining the correlation with advanced liver fibrosis revealed that HBsAg level is a significant factor in univariate analysis and is the only independent factor in multivariate analysis (Coefficient: -0.975, P = 0.039, OR: 0.377, 95% CI: 0.149-0.953). CONCLUSIONS HBsAg level varied with different clinical or virological categories. Lower baseline levels of HBsAg might reflect the status of advanced liver fibrosis in HBeAg positive chronic hepatitis B patients.

The Application of Liver Stiffness Measurement in Residents Without Overt Liver Diseases Through a Community-Based Screening Program.

AbstractThe application of liver stiffness measurement (LSM) by transient elastography (TE) in general population remains to clarify. This cohort study aimed to examine the usefulness of TE and to identify factors associated with significant liver fibrosis in community-based population.We conducted a hepatitis screening program in 2 remote villages of Southern Taiwan. All residents participated voluntarily and received questionnaire evaluation, blood tests, abdominal sonography, and LSM by TE. Residents with any one of following criteria including hepatitis B virus infection, hepatitis C virus infection, more than moderate alcohol drinking, and failure to obtain valid or reliable LSM were excluded.There were 831 residents participated in program. The valid and reliable LSM were obtained in 98.3% and 96.3% of residents, respectively. Finally, a total of 559 residents including 283 residents with nonalcoholic steatotic fatty liver disease (NAFLD) were enrolled for analysis. The mean liver stiffness was 4.9 ± 1.9 kPa. The liver stiffness increased in residents with diabetes mellitus (DM), higher body mass index (BMI), hypertension, abnormal waist–hip circumference ration (WHR), higher waist circumference (WC), and presence of fatty liver. Higher body weight, higher BMI, higher WC, abnormal WHR, abnormal aspartate aminotransferase (AST), abnormal alanine aminotransferase (ALT), and DM were the factors associated with significant fibrosis (liver stiffness ≥7 kPa) in either all participants or NAFLD residents. As determined by multivariate analysis, abnormal AST values and DM were the 2 independent factors in all participants (abnormal AST: OR 3.648, 95% CI 1.134–11.740, P = 0.03; DM: OR 2.882, 95% CI 1.282–6.478, P = 0.01) and in residents with NAFLD (abnormal AST: OR 4.197, 95% CI 1.154–15.262, P = 0.03; DM: OR 3.254, 95% CI 1.258–8.413, P = 0.02).LSM by TE is a useful screening tool in community. In residents, who were absence of chronic hepatitis virus infection or consumed less than moderate alcohol drinking, exhibited DM or abnormal AST values may consider a substantial group with significant fibrosis in community.

Lipoprotein lipase liberates free fatty acids to inhibit HCV infection and prevent hepatic lipid accumulation

Lipoprotein lipase (LPL) has been identified as an anti‐hepatitis C virus (HCV) host factor, but the cellular mechanism remains elusive. Here, we investigated the cellular mechanism of LPL involving in anti‐HCV. The functional activation of peroxisome proliferator‐activated receptor (PPAR) α signal by LPL transducing into hepatocytes was investigated in HCV‐infected cells, primary human hepatocytes, and in HCV‐core transgenic mice. The result showed that the levels of transcriptional transactivity and nuclear translocation of PPARα in Huh7 cells and primary human hepatocytes were elevated by physiologically ranged LPL treatment of either very‐low density lipoprotein or HCV particles. The LPL‐induced hepatic PPARα activation was weakened by blocking the LPL enzymatic activity, and by preventing the cellular uptake of free unsaturated fatty acids with either albumin chelator or silencing of CD36 translocase. The knockdowns of PPARα and CD36 reversed the LPL‐mediated suppression of HCV infection. Furthermore, treatment with LPL, like the direct activation of PPARα, not only reduced the levels of apolipoproteins B, E, and J, which are involved in assembly and release of HCV virions, but also alleviated hepatic lipid accumulation induced by core protein. HCV‐core transgenic mice exhibited more hepatic miR‐27b, which negatively regulates PPARα expression, than did the wild‐type controls. The induction of LPL activity by fasting in the core transgenic mice activated PPARα downstream target genes that are involved in fatty acid β‐oxidation. Taken together, our study reveals dual beneficial outcomes of LPL in anti‐HCV and anti‐steatosis and shed light on the control of chronic hepatitis C in relation to LPL modulators.

Prediction of early hepatocellular carcinoma recurrence using germinal center kinase-like kinase

Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.

Clinical utility of hepatitis B surface antigen kinetics in treatment-naïve chronic hepatitis B patients during long-term entecavir therapy

AIM To investigate the utility of hepatitis B surface antigen (HBsAg) kinetics in chronic hepatitis B patients during long-term entecavir treatment. METHODS This retrospective study included treatment-naïve chronic hepatitis B patients who received at least 2 years of consecutive entecavir treatment. Patients were followed up at three to six month intervals with liver biochemistry, hepatitis B virus DNA, and abdominal sonography. In hepatitis B e antigen (HBeAg)-positive patients, HBeAg levels were assessed every three to six month until results became negative. Serum HBsAg levels were determined at the baseline, one-year and five-year time points. Liver cirrhosis was diagnosed through liver biopsy, imaging examinations, or clinical findings of portal hypertension. Hepatocellular carcinoma was diagnosed by histological examination or dynamic image studies. RESULTS A total of 211 patients were enrolled. The median treatment time was 5.24 (2.00-9.62) years. Multivariate analysis showed that lower baseline HBsAg levels were associated with an earlier virological response, earlier hepatitis B e antigen (HBeAg) seroconversion, and earlier biochemical response in HBeAg-positive patients (cut-off value: 4 log IU/mL) and an earlier virological response in HBeAg-negative non-cirrhotic patients (cut-off value: 2.4 log IU/mL). Although HBsAg levels decreased slowly during long-term entecavir treatment, higher HBsAg decrease rates were found in the first year for HBeAg-positive non-cirrhotic patients, and patients with higher baseline HBsAg levels. More favorable clinical outcomes were not observed by a rapid HBsAg decline per se, but depended on lower baseline HBsAg levels. CONCLUSION Baseline HBsAg can be used to predict treatment responses. HBsAg levels and decrease rates should be considered together according to disease status while interpreting HBsAg changes.

The characteristics of residents with unawareness of hepatitis C virus infection in community

Background Control of hepatitis C virus infection (HCV) is an increasingly important issue. Enhancing screening coverage is necessary to discover more HCV infected subjects in community. However, a substantial population is unaware of HCV infection that needs more attention. Aim The aims of this study were to evaluate the status of HCV infected residents in remote villages, to compare characteristics between already known and unaware HCV infection subjects, and to analyze the disease insights. Patients and methods Screening intervention for liver diseases was conducted in remote villages of Tainan City of southern Taiwan from August 2014 to July 2016. Items of screening examinations included questionnaire, blood sampling for liver tests and viral hepatitis markers (hepatitis B surface antigen and anti-HCV antibody), abdominal sonography survey, and liver stiffness measurement by transient elastography. Quantitation of HCV RNA was measured for residents with positive anti-HCV antibody. Results A total of 194 (13.5%) out of 1439 participants showed positive for anti-HCV antibody. HCV viremia was detected in 119 (61.3%) residents. Previously unaware HCV infection by questionnaire record was present in 68 (35.1%) of ant-HCV positive residents. By multivariate logistic analysis, unaware HCV infected residents exhibited significantly mild liver fibrosis (OR 0.876, 95% CI 0.782~0.981, p = 0.022), more prevalent of heart diseases (OR 6.082, 95% CI 1.963~18.839, p = 0.002), and less cluster of family history of liver diseases (OR 0.291, 95% CI 0.113~0.750, p = 0.011) when comparing with already known HCV infected residents. Among the 126 already know HCV infected residents, only 59 (46.8%) received antiviral treatment or regular follow-up. No concept or no willing to receive medical care was observed in 44 (34.9%) residents. Conclusion In HCV endemic villages of Taiwan, residents with unaware HCV infection comprised about one third of HCV infected residents and exhibited obscure characteristics to identify. Less than half of already known HCV infected residents received adequate medical care. To eliminate HCV infection, vigorous efforts on enhancing screening coverage, educating update knowledge of liver diseases, and linking to medical care are urgently needed.

Favorable Response to Long-term Nucleos(t)ide Analogue Therapy in HBeAg-positive Patients with High Serum Fucosyl-Agalactosyl IgG

Aberrant IgG glycosylation is a feature of hepatitis B virus (HBV) infection but its effect on a long-term efficacy of antiviral therapy has never been addressed. After a screening of 1,085 patients, 132 eligible HBV e antigen (HBeAg)-positive and 101 HBeAg-negative patients with anti-HBV nucleos(t)ide analogue monotherapy were enrolled with on-treatment follow-ups for at least one year. IgG1 N-glycome was profiled using mass spectrometry and evaluated for its relevance in treatment responses. The results indicated that a high level of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) at baseline was associated with the severity of liver inflammation and damage but advanced treatment responses, including HBV DNA loss, HBeAg seroconversion, a reduced drug resistance rate, and a liver histological improvement at year 1, thereby improving the long-term treatment efficacy and the probability of treatment discontinuation in HBeAg-positive patients. Stepwise Cox regression analyses revealed that baseline IgG1-G0F >30% was an independent factor that links to virological response (HR 3.071, 95% CI 1.835–5.141, P < 0.001) or HBeAg seroconversion (HR 2.034, 95% CI 1.011–4.093, P = 0.046). Furthermore, a high IgG1-G0F level at the treatment endpoint was associated with an off-treatment sustained virological response. In conclusion, IgG1-G0F favors the medication outcome for HBeAg-positive chronic hepatitis B.