HBV-related Chronic Liver Disease Research Articles

Prevalence of chronic liver disease among young/middle-aged adults in Northern Italy: role of hepatitis B and hepatitis C virus infection by age, sex, ethnicity

BackgroundSparse population-based data are available on the prevalence and etiology of chronic liver disease (CLD) in Italy. The study aims to assess the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in CLD according to age, gender and ethnicity. MethodsClinically diagnosed CLD in the general population aged 20–59 years in the Veneto Region (North-Eastern Italy) were identified through the Adjusted Clinical Groups System, by record linkage of the archive of subjects enrolled in the Regional Health System with Hospital Discharge Records, Emergency Room visits, Chronic disease registry for copayment exemptions, and the Home care database. Age-standardized prevalence rates (PR) were computed in Italians and immigrants, based on country of citizenship. ResultsOverall 22,934 subjects affected by CLD in 2016 were retrieved, 21% related to HBV and 43% to HCV infection. The prevalence of HCV-related CLD was higher in males, peaking at 50–54 years (males = 11/1000; females = 4/1000). The PR of HBV-related CLD was almost negligible in the Italian population (1/1000), and higher among immigrants, especially from East Asia (males = 17/1000; females = 11/1000) and Sub-Saharan Africa (males = 13/1000; females = 10/1000). ConclusionSpecific population sub-groups identified by age, gender, and ethnicity, were demonstrated to be at increased risk, and these trends are in line with global epidemiological patterns of viral hepatitis.

Association of HLA-DQ and IFNL4 polymorphisms with susceptibility to hepatitis B virus infection and clearance

Background and aim. Leukocyte antigen DQ (HLA-DQ) and interferon-λ4 (IFNL4) gene polymorphisms were associated with susceptibility to chronic hepatitis B and C virus infection. This study further confirmed that variants of these genes were associated with susceptibility and spontaneous clearance of HBV infection in a Chinese population.Material and methods. A total of 1,069 subjects were recruited and divided into three groups i.e. 397 with CLD (HBV-related chronic liver disease), 434 with SC (spontaneous clearance), and 238 HC (healthy controls). HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917SNPs were genotyped using the Sequenom MassARRAY MALDI-TOF system.Results. HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted p = 0.0003) and with natural clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted. However, there was no association between IFNL4 polymorphism and HBV susceptibility or natural clearance (all p > 0.05). The multjfactor dimensionality reduction (MDR) test with permutation correction showed that a three-way interaction between IFNL4 and HLA-DQ SNPs was identified for HBV susceptibility (permutation p = 0.009 for the best factor model) and clearance (permutation p = 0.014 for the best factor model).Conclusions. The data from the current study provided additional evidence for an SNP-SNP interaction between HLA-DQ and IFNL4 in regulation to HBV infection and natural clearance.

Geographical pattern of chronic liver diseases in Italy: Results from two pooled national surveys

BackgroundThe information on the geographical characteristics of chronic liver diseases (CLD) in Italy is out-dated. AimTo provide up-dated information on the geographical pattern of patients with CLD born in Italy. MethodsPatients with CLD were enrolled in two national surveys performed in 2001 and 2014, which prospectively recruited subjects aged ≥18 years referring to Italian liver units located throughout the country that apply a similar clinical approach and analytical methods. ResultsThe total number of patients enrolled was 11,676. Alcohol-related CLD was more frequently observed in northern/central areas (25.0% vs. 20.7%, p < .001), while HBV-related (15.4% vs. 13.3%, p = .02) and HCV-related (71.2% vs. 67.1%, p < .001) CLD prevailed in southern areas/main islands (Sicily and Sardinia). These differences were stable over time. Liver cirrhosis without HCC was diagnosed more frequently in southern area/islands than in northern/central areas (23.7% vs. 18.8%, p < .01). Moreover, an increased proportion over time of patients with cirrhosis without HCC was observed both in northern/central areas (17.3% vs. 27.4%, p < .01) and in southern area/islands (22.6% vs. 27.9%, p < .01). ConclusionsThese up-dated findings show different geographical patterns of CLD in Italy, reflecting different behavioural habits and socio-economic conditions across the country. They may be useful to apply more adequate preventive measures and to allocate economic resources.

Transient Elastography- a Non-invasive Alternative to Upper Endoscopy for Detection of Gastric and Esophageal Varices in HBV and HCV Cirrhosis

Introduction: Esophageal and gastric varices are one of the most important complications of liver cirrhosis leading to Upper GI Bleed with a significant mortality and morbidity. Upper endoscopy is the currently recommended method for variceal screening and treatment to prevent upper GI bleed. However this method is invasive and carries a small but definitive risk of complications as well as an incremental expense. Non invasive methods to detect patients with large esophageal varices at high risk for bleeding are desirable. In this respect, several clinical, biological, ultrasonographic and elastrographic (transient elastography-TE) methods have been proposed Some of these have been validated as non-invasive alternatives to endoscopy Our study was done with the objective of studying the validity of liver stiffness measurement by fibroscan to predict the presence of esophageal and gastric varices in cirrhotic patients due to hepatitis C and B infection Methods: A retrospective analysis of medical records of 75 patients who underwent fibro scan and then screening endoscopy was carried out. This data was then analyzed to correlate the fibroscan findings with the presence of esophageal and gastric varices. Patients aged 18 to 80 years with HCV and HBV related chronic liver disease were included in this study. Patients with Hepatocellular carcinoma and cirrhosis due to non- HBV/ HCV related liver disease were excluded. Results: The results produced from this data shows that there is a significant association between liver stiffness measured during transient elastography and the presence of esophageal varices. .The results also show that fibro scan score is a better predictor of esophageal varices then gastric varices. There is no strong association between gastric varices and fibro scan score. So fibro scan can be used as screening for only esophageal varices and not for gastric varices Conclusion: The results produced from this data shows that there is a significant association between fibro scan score and esophageal varices. This shows that a non invasive modality like fibroscan score can be used as a screening tool for presence and degree of esophageal varices in patients with chronic hepatitis B and C. The results also show that fibro scan score is a better predictor of esophageal varices then gastric varices.

Prediction model of the progression of patients with acute deterioration of hepatitis B virus-related chronic liver disease to acute-on-chronic liver failure

This study aimed to establish a new model for predicting acute-on-chronic liver failure (ACLF) (defined by the Chinese Medical Association), which potentially occurs among patients with acute deterioration (AD) of hepatitis B virus (HBV)-related chronic liver disease (CLD).A total of 754 patients with AD of HBV-related CLD (total bilirubin (TBIL) > 51.3 μmol/L and prothrombin activity (PTA) < 60%, 40% < PTA < 60% when TBIL ≥ 171.1 μmol/L) were retrospectively analyzed and divided into a training cohort (580 patients) and a validation cohort (174 patients). The ACLF occurrence probability of these patients was statistically analyzed within 4 weeks. In the training cohort, multivariate logistic regression analysis was performed to determine the independent predictors of ACLF occurrence and to develop a new prediction model. The validation cohort was utilized to verify and evaluate the value of the new prediction model.Within 4 weeks, 9.9% of the patients progressed to ACLF (12.0 ± 6.7 days). The new prediction model was characterized by R = 3.090 + 0.035 × Age (years) − 0.050 × PTA (%) + 0.005 × TBIL (μmol/L) + 0.044 × D/T (%) − 0.072 × Na (mmol/L) + 0.180 × HBV DNA (log10IU/mL). The areas under the receiver operating characteristic curves of the training and validation cohorts in the new model were higher than those in the model for end-stage liver disease.The new prediction model could be used by clinicians to recognize patients with AD of HBV-related CLD with high risks of progressing to ACLF.

3. Study on lipid profile among adults with HBV and HCV related chronic liver diseases in Bangladesh-report from a tertiary centre

Background and Aims: Chronic Hepatitis B and C are the major causes of cirrhosis of Liver and Hepatocellular carcinoma in Bangladesh. Development of cirrhosis of liver result in derangement of metabolic functions. This study was conducted to find out the changes of lipid profile among adult with Chronic Viral Hepatitis B and C. Methods: This was cross sectional descriptive study in Medicine Inpatient Department of Rajshahi Medical College Hospital from June 2015 to july 2016. Total Number of Patients were 130. Among them 114 Chronic Hepatitis B and 16 patients chronic Hepatitis C. Age 18–65 years. Male 107, female 23. There were no comorbidities of these patients. Results: Among 130 Patients (116 Child's Pugh A & 14 Child's Pugh B). In HBV group Male 96, Female 18 and in HCV group Male 11, Female 05. Serum Total cholesterol, HDL, LDL and Serum Triglyceride were done in all patients in six monthly intervals. The results were reduction of Serum Total Cholesterol and HDL in 45 (39.47%) and increased Serum Triglyceride in 11 (09.65%) patients in HBV group. In HCV group increased Serum Total cholesterol and Serum Triglyceride in 07 (43.75%) and reduction of HDL in 03 (18.75%) patients. Conclusion: Developing countries like Bangladesh are likely to face an enormous burden of CLD and prevention and early diagnosis is essential to reduce economic loss and health system burden. Dyslipidemia is frequent in CLD & found with severity of the disease. Moreover, it may acts as a good predictor of CLD management. Till now, no needful studies are available in Bangladesh. Understanding the pattern of Dyslipidemia of hepatitis B & C related CLD in Bangladesh may enrich the clinician and may act as a baseline study for further research. The authors have none to declare.

Discussion and evaluation of diagnostic criteria for hepatitis B virus-related acute-on-chronic pre-liver failure

Objective: To investigate the concept of hepatitis B virus (HBV)-related acute-on-chronic pre-liver failure (pre-ACLF), and to develop and evaluate the diagnostic criteria for this disease. Methods: A retrospective analysis was performed for the clinical data of 754 patients with severe acute exacerbation (SAE) of HBV-related chronic liver disease, and their clinical features were identified. A multivariate logistic regression analysis was used to determine the risk factors for acute-on-chronic liver failure (ACLF). The inclusion rate of patients with SAE-HBV-related chronic liver disease and the detection rate of ACLF patients were analyzed to evaluate the value of four different versions of diagnostic criteria for pre-liver failure. The t-test, an analysis of variance, the Mann-Whitney U test, and the chi-square test were used for statistical analysis based on data type. Results: The incidence rate of ACLF in the patients with SAE-HBV-related chronic liver disease was 9.9% and the time to progression to ACLF was 12.0 ± 6.7 days. The multivariate logistic regression analysis showed that HBV reactivation (odds ratio [OR] = 5.118), direct bilirubin ratio (D/T) (OR = 1.041), age (OR = 1.033), total bilirubin (TBil) (OR = 1.005), prothrombin activity (PTA) (OR = 0.880), and serum sodium (Na) (OR = 0.918) were independent risk factors for ACLF. Group B (51.3 μmol/L < TBil < 171.1 μmol/L and 40%≤PTA < 60%, 4.2%) had a significantly lower incidence rate of ACLF than group A (51.3 μmol/L < TBil < 171.1 μmol/L and PTA < 40%, 13.7%) and group C (TBil > 171.1 μmol/L and 40% < PTA < 60%, 20.3%) (P < 0.001). Group C had a significantly shorter time to progression to ACLF than group A (10.5 ± 6.1 days vs 15.6 ± 7.4 days, P = 0.008). A total of 45 patients met the diagnostic criteria developed by Chongqing and the incidence rate of ACLF was 2.2%; 154 patients met the diagnostic criteria developed by Zhejiang and the incidence rate of ACLF was 7.1%; 188 patients met the diagnostic criteria in the Chinese guidelines and the incidence rate of ACLF was 6.4%; 117 patients met the diagnostic criteria for SAE-CHB and the incidence rate of ACLF was 9.4%. Conclusion: At present, these four versions of diagnostic criteria for pre-liver failure are not fully applicable to the clinical practice in China. The diagnostic criteria for HBV-related pre-ACLF should include important assessment indices which affect its progression to ACLF.

HBV genome analysis in the progression of HBV related chronic liver disease

HBV genome analysis in the progression of HBV related chronic liver disease

Association of HLA-DQ and IFNL4 polymorphisms with hepatitis B virus infection and clearance

Objective: To confirmed the polymorphisms of HLA-DQ and IFNL4 were associated with HBV infection and clearance in a Chinese population. Methods: The Sequenom MassARRAY MALDI-TOF system was used to genotype the HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917. A binary logistic regression test was conducted to estimate the relative risk of these SNPs with HBV infection and clearance. Haploview4.2 software and PHASE software (v2.0.2) were employed to analyze linkage disequilibrium (LD) and haplotype frequencies. The MDR program was applied to analyze interactions between SNP and SNP.Statistical analysis was performed using SPSS 19.0 and P-values were corrected by Bonferroni's corrections. Results: A total of 1,069 subjects were recruited and divided into three groups: 238 healthy controls(HC), 397 with HBV-related chronic liver disease (CLD), 434 with spontaneous clearance (SC). The rs9275319TT was most frequently identified among all groups(86.2% in the CLD group, 77.6% in the SC group, and 75.9% in the HC group).Carriage of the rs9275319 C allele was a protective factor for chronic HBV infection (the allele model: P = 0.000 3, OR,0.514; 95% CI, 0.359-0.738) and clearance (the allele model: P = 0.002, OR, 1.659; 95% CI, 1.197-2.300). HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted P = 0.000 3) and spontaneous clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted P = 0.002). However, there was no association between IFNL4 polymorphism and HBV infection((allele model: P = 0.082 for rs368234815; P = 0.063 for rs12971396; P = 0.517 for rs12979860; P =0.695 for rs8099917) or spontaneous clearance ((allele model: P = 0.358 for rs368234815; P = 0.105 for rs12971396; P = 0.640 for rs12979860; P = 0.640 for rs8099917;all P > 0.05). The multifactor dimensionality reduction (MDR) test showed there was a three-way interaction (rs12971396, rs12979860, and rs9275319) between IFNL4 and HLA-DQ polymorphisms for HBV infection (permutation P = 0.009 for the best factor model) and clearance (permutation P = 0.014 for the best factor model). Conclusion: The SNP-SNP interaction between HLA-DQ and IFNL4 is associated with the regulation of HBV infection and natural clearance.

Bone Health and Impact of Tenofovir Treatment in Men with Hepatitis-B Related Chronic Liver Disease

Chronic Liver Disease (CLD) has been shown to have an adverse impact on bone health. Hepatitis-B related CLD and its treatment with tenofovir may have additional effects on skeleton. To study the impact of HBV related CLD and its treatment with Tenofovir on bone health in Indian subjects. This cross sectional study included men (18-60 years) and comprised of three groups: Group-1 was treatment naïve HBV related CLD (n=79), Group-2 those with HBV related CLD on tenofovir for at least 1 year (n=136), Group-3 age, sex and Body Mass Index (BMI) matched healthy controls (n=58). Bone biochemistry and Bone Mineral Density (BMD) at spine, Femoral Neck (FN) and forearm were studied. Independent t-test or ANOVA was used to compare the means of continuous variables and chi-square test for categorical variables. Multiple logistic regression was used to assess the factors causing Low Bone Mass (LBM) at FN. A significantly greater proportion (P<0.05) of patients (40%) with CLD (group 1 and group 2) had vitamin D deficiency (<20ng/ml) in comparison with control group (22%). The mean serum C-Terminal telopeptide was significantly higher (P<0.05) and the mean BMD was significantly lower (P<0.05) in subjects with HBV related CLD than controls. The prevalence of LBM was higher in group 1 at the spine (31%) and forearm (18.4%) when compared to controls (8.1% and 7.8% respectively) (P<0.05). The proportion of patients with LBM at FN was highest in group 2 (12.3%) compared to those in group 1 (8%) and group 3 (4%) (P<0.05). Advanced age, low BMI, and high viral load (>10,000IU/ml) emerged as significant risk factors for LBM at FN. The impact of hepatitis-B related CLD as well as its treatment on bone health is significant. Bone health need to be periodically evaluated in these subjects especially in older men who are lean and have a higher viral load.

Non-invasive assessment of liver fibrosis in patients with HBV-related chronic liver disease undergoing antiviral treatment: A preliminary study

In chronic hepatitis B (CHB) patients, fibrosis assessment during antiviral treatment is a key step in the clinical management. Aim of this study was to evaluate the performance of elastography in assessing fibrosis stage in CHB before and after two years of nucleoside/nucleotide analogues (NUC) treatment in comparison with indirect serum markers. CHB diagnosis was made according to standard criteria. A clinical and virological evaluation was performed at baseline and again at 3, 6, 9, 12 18, and 24 months during treatment. Fibrosis was evaluated by liver biopsy, elastography and indirect serum markers. Of 75 patients, 50 had CHB, HBeAg negative and were deemed eligible for this study. Of these, 22 underwent liver biopsy. Mean histo-morphometric values of fibrotic tissue differed significantly in the stage < S3 vs. stage ≥S3: 2.01±2.62% vs. 12.85±7.31% (p=0.03), respectively. At 18 and 24 months, stiffness values were statistically reduced from those previously observed (P=0.03 and P<0.001). At 24 months the values of APRI, FIB-4 and LOK were not different from baseline values, while the value of FORNS score at 24 months was the only one statistically reduced. In two patients with fibrosis stage S3 and S6, respectively, fibrosis regressed to stage S2 and S5. In conclusion, the results of the present study show that liver histology, stiffness and FORNS score improve significantly during a long-term follow-up of HBV patients successfully treated with NUC. These results strongly suggest that the non-invasive evaluation of liver fibrosis represents a key step in the management and treatment of chronic HBV hepatitis.

T cell regulation in HBV-related chronic liver disease

T cell regulation in HBV-related chronic liver disease

Serum ischemic modified albumin (IMA) concentration and IMA/albumin ratio in patients with hepatitis B-related chronic liver diseases.

Albumin is the most important protein synthesized by the liver. Posttranscriptional changes occur in the molecular structure of albumin due to various factors and isoforms arise. Ischemic modified albumin (IMA) is one such isoform. This study was conducted to evaluate serum IMA concentrations in patients with hepatitis B virus (HBV)-related chronic liver diseases. This study included 74 treatment-naive chronic hepatitis B patients, 25 patients with HBV-related cirrhosis, and 49 healthy controls. Serum IMA concentration was measured spectrophotometrically using the albumin cobalt binding test. The mean IMA concentrations in the chronic hepatitis B group and healthy controls were 0.33 ± 0.11 ABSU and 0.27 ± 0.70 ABSU, respectively, and the difference was statistically significant (P < 0.001). Mean IMA/albumin ratios (IMAR) in the chronic hepatitis B and control groups were 0.08 ± 0.04 and 0.06 ± 0.17, respectively, and the difference was also statistically significant (P < 0.001). Higher serum IMA concentrations and IMAR were detected in patients with advanced fibrosis. Serum IMA concentration and IMAR are increased in patients with HBV-related chronic liver diseases and IMA and IMAR are associated with the degree of liver fibrosis. IMA and IMAR may have potential use as noninvasive markers of fibrosis in chronic hepatitis B patients.

Hepatitis A, B, and C

1. John C. Christenson, MD* 2. John J. Manaloor, MD* 1. *Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN. Because hepatitis A, B, and C viruses are responsible for substantial morbidity and mortality, clinicians must learn to recognize, treat and prevent infections caused by these viruses. After completing this article, readers should be able to: 1. Describe the epidemiology of hepatitis A, B, and C virus infections. 2. Recognize the clinical features of hepatitis A infection. 3. Appropriately administer vaccines for the prevention of hepatitis A and B infection. 4. Recognize the various antiviral regimens used for the treatment of hepatitis B and C liver disease. 5. Order the most appropriate tests for the diagnosis of hepatitis virus infections. During the past 30 years, the understanding of hepatitis viruses has greatly expanded. Knowledge of hepatitis has progressed from merely describing the various clinical syndromes to a greater understanding of the pathogenesis of disease caused by these viruses and the development of chronic infection that eventually leads to cirrhosis or hepatocellular carcinoma. Expanded understanding also has led to the development of effective vaccines against hepatitis A virus (HAV) and hepatitis B virus (HBV) and antiviral therapies against hepatitis C virus (HCV). The introduction of routine vaccination against HAV and HBV starting in early childhood in the United States has resulted in a substantial decrease in both of these infections in children and the subsequent complications of HBV-related chronic liver disease. Effective screening of mothers during pregnancy and the administration of HBV vaccine soon after birth, along with administration of hepatitis B immune globulin (HBIG) to infants born to women who have HBV infection, has led to near eradication of perinatally acquired HBV disease in the United States and other countries with effective screening programs. The introduction …

Hepatitis B virus infection in children of HBV-related chronic liver disease patients: a study of intra-familial HBV transmission.

HBV-infected patients are potential sources of intra-familial transmission. We studied HBV transmission and molecular characteristics within families of HBV-related chronic liver disease (CLD) patients. Family members [index cases (ICs), spouses, and 1-18-year-old children] of HBV-related CLD patients were tested for HBsAg, anti-HBc, and anti-HBs. HBsAg-positive subjects were tested for HBeAg/anti-HBe. Anti-HBc-positive children together with their family members were further investigated for HBV DNA. Sequences of positive isolates were analyzed over surface, precore (PC) and basal core promoter (BCP) regions. Among 94 children of 46 ICs, the prevalence of HBsAg, anti-HBc, and anti-HBs was 10 (10.6%), 19 (20.2%), and 46 (48.9%), respectively. Thirty-eight (40.4%) children were seronegative, indicating susceptibility to HBV infection. HBV DNA was identified in all ICs, 4 spouses, and 16 children. Having both parents with HBsAg positive and at least two HBV carriers in the households were significant risk factors of intra-familial transmission. HBV genotype/subtype distributions were comparable between children and ICs/spouses, with predominance of genotype B. The majority of HBV DNA sequences found in children were identical to their corresponding ICs-particularly mothers-including mutation patterns in the surface, PC, and BCP regions. Recognized mutations associated with HBsAg detection and/or vaccination failure, T140I, T143S/M, G145R, and Y161F, were identified in 20 subjects; while mutations linked to HBeAg-defective variants, PC G1896A and BCP A1762T/G1764A, were found in 7 and 11 subjects, respectively. Children of HBV-related CLD patients were at increased risk of HBV infection through multi-modal transmission routes despite negative parental HBsAg and HBeAg status.

Effects of interaction between genetic variants in human leukocyte antigen DQ and granulysin genes in Chinese Han subjects infected with hepatitis B virus.

Single nucleotide polymorphisms (SNPs) of HLA-DQ and granulysin (GNLY) are reportedly associated with HBV infection. The aim of this study was to investigate the effects of interactions between SNPs in HLA-DQ and GNLY on the outcome of hepatitis B virus (HBV) infection in Chinese Han subjects. HLA-DQ (rs9275572) and GNLY (rs1866139 and rs11127) were genotyped in 310 subjects with HBV-related chronic liver disease, 295 in whom spontaneous clearance of HBV had occurred and 316 who had not been exposed to HBV. HLA-DQ rs9275572 was significantly correlated with HBV clearance (dominant genetic model: OR, 1.84; 95% CI, 1.30-2.61; adjusted P = 0.001). There was no statistical association of GNLY rs1866139 and rs11127with HBV infection outcomes. However, significant sex-specific associations with HBV susceptibility were observed in men who carried rs1866139 CG or rs11127 TC and in women who carried rs1866139 GG or rs11127 CC. The findings were the same in the validation cohort, which was composed of 829 subjects. Based on a multifactor dimensionality reduction test with permutation correction, a three-way interaction between SNPs in HLA-DQ and GNLY was identified in terms of HBV clearance. In conclusion, additional evidence for an association of HLA-DQ and GNLY SNPs with HBV infection outcomes has been identified and a SNP-SNP interaction between HLA-DQ and GNLY on HBV clearance observed.

HBV-related chronic liver disease and insulin resistance

HBV-related chronic liver disease and insulin resistance

Reappraisal of serum alpha‐foetoprotein as a surveillance test for hepatocellular carcinoma during entecavir treatment

The aim of this study was to re-evaluate the diagnostic performance of alpha-foetoprotein (AFP) as a surveillance test for hepatocellular carcinoma (HCC) in patients with hepatitis B virus-related chronic liver disease who were treated with entecavir (ETV). Between January 2007 and August 2012, we analysed 373 treatment-naïve patients with HBV-related chronic hepatitis (n = 229) or cirrhosis (n = 144) who were candidates for surveillance test, and were treated with ETV (0.5 mg/day) for longer than 12 months. To minimize the effect of AFP elevation caused by hepatitis activity, serum AFP levels were measured 12 months after the initiation of ETV treatment. Hepatocellular carcinoma developed in 28 patients (7.5%) during a median follow-up period of 48.0 months (IQR = 40.5-57.3 months). The area under the receiver operating characteristic curve for AFP was 0.71 (95% CI = 0.59-0.84). The optimal AFP cut-off value was 13 ng/ml, leading to a sensitivity of 50.0%, specificity of 98.8%, positive predictive value of 77.8% and negative predictive value of 96.1%. In multivariate Cox analysis, an older age, the presence of cirrhosis and AFP levels of ≥20 ng/ml at 12 months after treatment were found to be significantly associated with an increased incidence of HCC. The role of serum AFP as a surveillance test should be re-evaluated in patients with HBV-related chronic liver diseases who were treated with antiviral therapy.

Reversible phospho-Smad3 signalling between tumour suppression and fibrocarcinogenesis in chronic hepatitis B infection

Transforming growth factor (TGF)-β, type I receptor (TβRI) and c-Jun N-terminal kinases (JNK) phosphorylate Smad3 differentially to create 2 isoforms phosphorylated (p) at the COOH-terminus (C) or at the linker region (L) and regulate hepatocytic fibrocarcinogenesis. This study aimed to compare the differences between how hepatitis B virus (HBV) infection affected hepatocytic Smad3 phosphorylated isoforms before and after anti-viral therapy. To clarify the relationship between Smad3 phosphorylation and liver disease progression, we studied 10 random patients in each stage of HBV-related fibrotic liver disease (F1-4) and also 10 patients with HBV-associated HCC. To examine changes in phosphorylated Smad3 signalling before and after anti-HBV therapies, we chose 27 patients with chronic hepatitis B who underwent baseline and follow-up biopsies at 52 weeks from the start of nucleoside analogue treatments (Lamivudine 100 mg daily or Telbivudine 600 mg daily). Fibrosis stage, inflammatory activity and phosphorylated Smad3 positivity in the paired biopsy samples were compared. Hepatocytic pSmad3C signalling shifted to fibrocarcinogenic pSmad3L signalling as the livers progressed from chronic hepatitis B infection to HCC. After nucleoside analogue treatment, serum alanine aminotransferase (ALT) and HBV-DNA levels in 27 patients with HBV-related chronic liver diseases were decreased dramatically. Decrease in HBV-DNA restored pSmad3C signalling in hepatocytes, while eliminating prior fibrocarcinogenic pSmad3L signalling. Oral nucleoside analogue therapies can suppress fibrosis and reduce HCC incidence by successfully reversing phosphorylated Smad3 signalling; even liver disease progressed to cirrhosis in chronic hepatitis B patients.

Recent insights into hepatitis B virus–host interactions

Hepatitis B virus (HBV) poses a threat to global public health mainly because of complications of HBV-related chronic liver disease. HBV exhibits a narrow host range, replicating primarily in hepatocytes by a still poorly understood mechanism. For the generation of progeny virions, HBV depends on interactions with specific host factors through its life cycle. Revealing and characterizing these interactions are keys to identifying novel antiviral targets, and to developing specific treatment strategies for HBV patients. In this review, recent insights into the HBV-host interactions, especially on virus entry, intracellular trafficking, genome transcription and replication, budding and release, and even cellular restriction factors were reviewed.