Search

Rare diseases, also known as orphan diseases, are a group of diseases that affect a relatively small number of people. Low incidence rates, atypical symptoms, imperfect diagnosis criteria and few treatment options impose medical, psychological and financial stress on the local healthcare system. The spectrum of liver diseases in China has changed in the past decades due to successful control of once highly prevalent viral hepatitis B and C. Furthermore, the increased awareness and improved availability of specific laboratory tests have also facilitated the diagnosis of rare diseases such as autoimmune, cholestatic and genetic liver diseases. Finally, considering the huge population, the total number of many rare liver diseases in China is not as rare as once deemed. In this mini-review article, we will outline the current clinical and epidemiological profiles of some rare liver diseases that are no longer rare in China.

Background Obesity is typically associated with metabolic dysfunction, but its impact on hepatocellular carcinoma (HCC) remains unclear in patients with chronic hepatitis B (CHB). Aim To study the effect of obesity on HCC development in patients with CHB receiving antiviral therapy. Methods We included patients from a Chinese multicentre, prospective, observational, treated CHB cohort in this study. General obesity was evaluated by body-mass index (BMI). Central obesity was evaluated by waist circumference, waist-to-hip ratio and waist-to-height ratio. Results A total of 5754 nucleos(t)ide analogue treated patients were enrolled in the analysis. The 5-year cumulative incidence of HCC was 2.9%. Waist-to-height ratio performed better in predicting HCC development than BMI, waist circumference or waist-to-hip ratio. Patients with central obesity (defined as waist-to-height ratio >0.5) had significantly higher 5-year incidence of HCC than those without central obesity in the overall population (3.9% vs 2.1%, hazard ratio [HR]: 2.06, P = 0.0001) and 745 propensity score matched pairs (4.7% vs 2.3%, HR: 2.04, P = 0.026), respectively. Besides cirrhosis status and aMAP HCC risk score, central obesity was also independently associated with HCC risk (HR: 1.63, P = 0.013). Waist-to-height ratio gain within 1 year was associated with a significantly higher HCC risk with an adjusted HR value of 1.88 (95% confidence interval: 1.12-3.13, P = 0.017). Conclusions Central obesity, evaluated by the waist-to-height ratio, was associated with a twofold increase in HCC risk among CHB patients receiving antiviral treatment, highlighting the important role of abnormal metabolic function in the progression of liver disease.

Background and Aim This single‐arm, open‐label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. Methods Treatment‐naive or interferon‐experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). Results Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post‐treatment course and 3 discontinued follow‐up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. Conclusions The all‐oral, ribavirin‐free regimen of seraprevir and sofosbuvir is an effective and well‐tolerated treatment option for Chinese patients mono‐infected with HCV, including those with a history of interferon treatment.

FoxA2 is an essential transcription factor for liver organogenesis and homeostasis. Although reduced expression of FoxA2 has been associated with chronic liver diseases, hepatic progenitor cells (HPCs) that are activated in these circumstances express FoxA2. However, the functional effects and underlying mechanism of FoxA2 in HPCs are still unknown. As revealed by immunostaining, HPCs expressed FoxA2 in human cirrhotic livers and in the livers of choline-deficient diet supplemented with ethionine (CDE) rats. Knocking down FoxA2 in HPCs isolated from CDE rats significantly increased cell proliferation and aerobic glycolysis. Moreover, gene transcription, protein expression, and the enzyme activities of hexokinase 2 (HK2) were upregulated, and blocking HK2 activities via 2-deoxyglucose markedly reduced cell proliferation and aerobic glycolysis. Kyoto Encyclopedia of Genes and Genomes analysis revealed that FoxA2 knockdown enhanced the transcription of genes involved in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and triggered downstream Akt phosphorylation. Blocking the PI3K/Akt pathway by Ly294002 inhibited HK2 activities, aerobic glycolysis, and cell proliferation in FoxA2-knockdown cells. Therefore, FoxA2 plays an important role in the proliferation and inhibition of HPCs by suppressing PI3K/Akt/HK2-regulated aerobic glycolysis.

BACKGROUND AND PURPOSE: The innate and adaptive immune systems both play important roles in drug‐induced liver injury (DILI). However, the crosstalk between the innate and adaptive immunity in DILI is largely unknown. Extensive crosstalk is likely mandated by co‐stimulatory interactions between these immune systems. OX40 is a co‐stimulatory molecule, but whether it regulates the intrahepatic immune response in DILI remains unknown. EXPERIMENTAL APPROACH: Acute liver injury was induced by paracetamol (acetaminophen), carbon tetrachloride (CCl(4)), and d‐galactosamine/LPS (GalN/LPS) in wild‐type (WT) and Ox40 knockout (KO) mice, and disease progress was compared. KEY RESULTS: Plasma OX40 levels were significantly increased and were augmented in intrahepatic CD4(+) T cells after paracetamol, CCl(4), or GalN/LPS administration. Liver injury in Ox40‐deficient mice was attenuated compared with that in WT mice. Compared with WT mice, hepatic infiltration of Th1 and Th17 cells and macrophages in Ox40 KO mice was reduced. Furthermore, adoptive transfer of Ox40 KO‐CD4(+) T cells to Rag1 (−/−) mice resulted in alleviated liver injury compared with WT‐CD4(+) T‐cell transfer, with reduced liver infiltration of macrophages and pro‐inflammatory cytokine secretion. Moreover, OX40/Fc stimulation in vitro revealed that soluble OX40 enhanced the biological function of murine macrophages, including up‐regulation of genes associated with inflammation and tissue infiltration. Finally, soluble OX40 levels were significantly elevated in DILI patients compared with healthy controls. CONCLUSION AND IMPLICATIONS: OX40 is a key molecule that promotes both pro‐inflammatory macrophage and CD4(+) T‐cell function, exacerbating paracetamol‐induced liver injury. OX40 could serve as a diagnostic index and therapeutic target of DILI.

Background To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). Aim To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. Methods We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed. Results We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10-4 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients. Conclusions CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.

AIM Chronic drug-induced liver injury (DILI) with persistent abnormal liver function tests (LFTs) >6 months after cessation of the insulting drugs could progress to cirrhosis. The aim of the present study was to identify the risk factors of chronic DILI for early recognition and better management. METHODS History of drug intake and results of LFTs were retrospectively retrieved for patients with a discharge diagnosis of DILI for at least 1-year follow up. The risk factors independently associated with chronic DILI were analyzed by multiple logistic regression analyses. RESULTS A total of 33 of the 140 DILI patients had persistent abnormal LFTs >6 months, which were considered as chronic DILI. It was found that the time intervals of alanine aminotransferase and total bilirubin decline from the peak to their half peak (T0.5ALT , T0.5TBIL ) were significantly longer in the chronic DILI group than that in the recovered group (P = 0.001 and P

The role of LOXL1 in fibrosis via mediating ECM crosslinking and stabilization is well established; however, the role of hepatic stellate cells (HSCs)-specific LOXL1 in the development of fibrosis remains unknown. We generated HSCs-specific Loxl1-depleted mice (Loxl1Gfap-cre mice) to investigate the HSCs-specific contribution of LOXL1 in the pathogenesis of fibrosis. Loxl1fl/fl mice were used as the control. Furthermore, we used RNA sequencing to explore the underlying changes in the transcriptome. Results of the sirius red staining, type I collagen immunolabeling, and hydroxyproline content analysis, coupled with the reduced expression of profibrogenic genes revealed that Loxl1Gfap-cre mice with CCl4 -induced fibrosis exhibited decreased hepatic fibrosis. In addition, Loxl1Gfap-cre mice exhibited reduced macrophage tissue infiltration by CD68-positive cells and decreased expression of inflammatory genes compared with the controls. RNA sequencing identified integrin α8 (ITGA8) as a key modulator of LOXL1-mediated liver fibrosis. Functional analyses showed that siRNA silencing of Itga8 in cultured fibroblasts led to a decline in the LOXL1 expression and inhibition of fibroblast activation. Mechanistic analyses indicated that LOXL1 activated the FAK/PI3K/AKT/HIF1a signaling pathway, and the addition of inhibitors of FAK or PI3K reversed these results via downregulation of LOXL1. Furthermore, HIF1a directly interacted with LOXL1 and upregulated its expression, indicating that LOXL1 can positively self-regulate by forming a positive feedback loop with the FAK/PI3K/AKT/HIF1a pathway. We demonstrated that HSCs-specific Loxl1 deficiency prevented fibrosis, inflammation and that ITGA8/FAK/PI3K/AKT/HIF1a was essential for the function and expression of LOXL1. Knowledge of this approach can provide novel mechanisms and targets to treat fibrosis in the future.

Background & aims Double-negative (DN) T-cell is a unique regulatory T-cell, which is essential for maintaining immune system homoeostasis. However, the role of DN T-cells in the pathogenesis of primary biliary cholangitis (PBC) is still unknown. Methods We investigated the number and function of DN T-cells in peripheral blood and liver biopsy specimens of PBC patients. Results The number and frequency of DN T-cells significantly decreased in peripheral blood and liver tissue of PBC patients. Furthermore, the frequency of DN T-cells in PBC was negatively correlated with disease severity and positively correlated with ursodeoxycholic acid response. In vitro assays showed that perforin expression and the suppressive capability of DN T-cells on the proliferation of CD4+ and CD8+ T-cells were impaired in PBC. Finally, lithocholic acid, the most hydrophobic acid, could downregulate the proliferation and perforin expression of DN T-cells. Conclusions Decreased quantity and function of DN T-cells in PBC may result in the loss of immune regulations on effector CD4+ and cytotoxic CD8+ T-cells, and thereby may break the immune tolerance and promote the pathogenesis of PBC.

Elastin is an amorphous protein highly resistant to elastase degradation and is believed to be the most stable component among the extracellular matrix (ECM) members. Thus the excessive deposition of elastin in advanced liver fibrosis may contribute to the declining reversibility of the disease. Our previous study has found that elastin crosslinking inhibition can effectively arrest liver fibrosis progression. To further understand the roles of elastin involved in liver fibrosis, we systematically investigated the expression, accumulation, and degradation based on dynamic and bidirectional CCl4 -induced liver fibrosis mouse models and visualized the ultrastructure of elastin globules in cultured LX-2 cells. We found that the expression pattern of tropoelastin (soluble elastin) and collagen I was not completely comparable at both the transcriptional and posttranscriptional levels during liver fibrosis progression and regression. Elastin mainly accumulated onto the internodular fibrous septa and enlarged portal areas and intertwined with collagen I at the late stage of liver fibrosis. Three-dimensional analysis of elastin and collagen I by confocal immunofluorescence coupled with biochemical analyses revealed that with respect to collagen, elastin deposition was characterized by late aggregation in progression and slow turnover in regression. In addition, we visualized the dynamic ultrastructure of ECM fibers during liver fibrogenesis and fibrolysis and the ultrastructure of elastin globules self-aggregated by tropoelastin crosslinking. Our current study established new general hallmarks of elastin levels and forms in progressive and regressive liver fibrosis and provided a foundation for further experimental investigation of the growing role of elastin in liver fibrosis regression.

Wisteria floribunda agglutinin-positive Mac-2-binding protein (M2BP) has been identified as a predictor for the response of interferon α (IFN-α) in patients with viral hepatitis. However, whether serum glycosylation isomer of M2BP (M2BPGi) was associated with the regression of liver fibrosis in patients with chronic hepatitis B (CHB) during IFN-α add-on therapy is still unknown. CHB patients were treated with entecavir for 26 weeks followed by entecavir plus pegylated IFN-α for 52 weeks. Liver biopsies were taken at baseline and treatment week 78. The regression of fibrosis was identified according to Ishak standard or Ishak plus Progressive-Indeterminate-Regressive (P-I-R) standard. Serum M2BPGi and liver function tests were measured at baseline and every 26 weeks of treatment. A total of 72 CHB patients were included in the present study. Serum M2BPGi was correlated with fibrosis and necroinflammation both at baseline and week 78. If Ishak standard was used as the reference, only the percent change of M2BPGi at week 52 from week 26 (Δ%M2BPGi26w-52W ) was independently associated with fibrosis regression at treatment week 78, the area under the ROC curve (AUROC) of Δ%M2BPGi26w-52W for predicting fibrosis regression was 0.705. As for Ishak plus P-I-R standard, the AUROC of the predictive model for fibrosis regression (0.896*M2BPGi52W + 0.363*necroinflammation score0w + 2.051*Ishak score0w - 4.489) was 0.888. These data indicated that dynamic changes of serum M2BPGi were associated with fibrosis regression in CHB patients on IFN-α add-on therapy.

BACKGROUND AND AIM The impact of male sex and past hepatitis B virus (HBV) infection on survival of primary biliary cholangitis (PBC) are issues at discussion. The aim of the present study was to identify risk factors for transplant-free survival (TRS) in Chinese PBC patients who received ursodeoxycholic acid (UDCA), with special focus on the impact of male sex and past HBV infection. METHODS We followed up PBC patients who received UDCA at our institute between January 2000 and December 2017 until their death, liver transplantation, or censored on April 1, 2018, by interview and review of medical records. We used Cox proportional hazards model and Kaplan-Meier method. RESULTS Out of 976 PBC patients, 732 UDCA-treated patients (female : male = 6.2:1) with required clinical and laboratory data were enrolled in this study. The median follow-up period were 4.8 years (interquartile range: 2.8-7.1 years). The overall 5-, 10-, and 15-year TRS rates were 86.7% (95% CI: 83.8-88.1), 71.1% (95% CI: 65.0-77.2), and 59.2% (95% CI: 44.5-73.9), respectively. The survival was significantly worse for male patients and older patients (≥ 55 years) (log-rank test: P

Background and purpose Diethyldithiocarbamate (DDC) is a major metabolite of disulfiram that is a potential drug for alcoholism treatment. In the present study, we attempted to explore the possible effect of DDC on non-alcoholic fatty liver disease (NAFLD) and related fibrosis in vivo. Experimental approach C57BL/6 mice and Sprague Dawley (SD) rats received a methionine/choline-deficient (MCD) diet to establish the model of NAFLD with or without DDC treatment. The livers and serum were assessed for histological changes and parameters related to lipid metabolism, liver injury, inflammation and fibrosis. Apoptosis and macrophage related markers were assessed by immunohistochemistry (IHC). Key results DDC significantly reduced hepatic steatosis in rats with NAFLD, induced by the MCD diet. DDC reduced the oxidative stress and endoplasmic reticulum stress-related parameters in mice with non-alcoholic steatohepatitis, induced by the MCD diet. IHC for Bax and cleaved caspase-3 showed that DDC inhibited the apoptosis of hepatocytes in the liver. DDC significantly reduced ballooning and Mallory-Denk bodies (MDB) in hepatocytes, accompanied by suppression of serum alanine aminotransferase, aspartate aminotransferase and MDB formation-related genes. DDC significantly alleviated hepatic inflammation, accompanied by suppression of inflammation-related genes. DDC suppressed the infiltration of macrophages, particularly inducible NOS-positive pro-inflammatory macrophages. In addition, DDC significantly alleviated liver fibrosis. Microarray analyses showed that DDC strongly affected lipid metabolism and oxidative stress-related processes and pathways. Conclusion and implications DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.

Background Globally, chronic hepatitis B (CHB) is a major public health concern. Timely and effective management can prevent disease progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC). Currently, there is no consensus on the clinical management of CHB in East Asia. Aim To establish an East Asia expert opinion on treatment initiation for CHB based on alanine aminotransferase (ALT) level, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, cirrhosis and HCC risk scores. Methods A meeting was held online with a panel of 10 experts from East Asia to discuss ALT, HBV DNA, cirrhosis and HCC risk scores. Indications for CHB treatment in the latest international guidelines were reviewed. Consensus was summarised to provide recommendations on the initiation of treatment for CHB. Results Anti-viral therapy is recommended for CHB patients with (a) HBV DNA ≥ 2000 IU/mL and ALT ≥ 1× upper limit of normal (ULN); (b) HBV DNA ≥ 2000 IU/mL, ALT 40 years. Patients with cirrhosis and/or HCC should be treated regardless of ALT levels if HBV DNA level is detectable. Initiating anti-viral therapy or close monitoring at 3-month intervals is recommended for CHB patients with at least two HCC risk factors. Conclusions These expert recommendations will contribute to a new standard of daily clinical practice in East Asia.

Myeloid cells infiltrate into the liver and differentiate into macrophages in different liver injury mouse models. However, the heterogeneity of bone marrow (BM)-derived LMs populations remains to be understood. To investigate this and understand the impact of the macrophage niche on the properties of recruited BM-derived macrophages, we used a non-myeloablation BM transplantation model to label and trace BM-derived LMs. Subsequently, we quantified the number of embryonic-derived liver-resident macrophages, BM-derived LMs and total LMs in CCl4 and irradiated acute liver injury mouse models, respectively. Finally, we compared the cell fate, gene expression patterns, chemokine signals, and surface markers of irradiated and CCl4 -treated BM-derived LMs. We observed that, as compared to CCl4, radiation generated a macrophage niche by depleting embryonic-derived liver-resident macrophages and induced the recruitment of BM-derived LMs that further settled in the liver. Irradiated and CCl4 -treated BM-derived LMs are different with respect to their cell fates, gene expression patterns, and chemokine expression and recruitment. They also have different surface markers shortly after differentiating from their progenitors. Our findings suggest that irradiated and CCl4 -treated LM populations derived from the bone marrow display different patterns of gene expression and phenotypes; these differences may be due to the availability of macrophage niche.

Background & aims Polygonum Multiflorum Thumb (PMT), an ancient anti-aging Chinese herb known traditionally as He Shou Wu, has side effects of liver toxicity. To determine the main clinical and pathological characteristics of liver toxicity induced by PMT and the clinical course after its cessation. Methods Data of patients, diagnosed as drug-induced liver injury and hospitalised in Beijing Friendship Hospital from August 2005 to August 2017, were retrospectively reviewed. Clinical, pathological data and outcome after cessation of He Shou Wu were obtained and analysed. Kruskal-Wallis and Chi-square (χ2 ) tests were performed. Results Twenty-nine patients with He Shou Wu-induced liver injury were enrolled. The median age was 53 years (range 15-74) and 75.9% (22/29) were women. The most common symptom was jaundice (79.3%, 23/29). Of nine patients with liver biopsies, six showed acute cholestatic hepatitis, two acute, and one chronic hepatocellular injury pattern. The latency, liver chemistries and outcomes were comparable between pure He Shou Wu (5 patients) and its compounds (24 patients). Twenty-five of 29 patients (86.2%) had normal serum alanine aminotransferase levels after 45 days (range: 10-138 days) and total bilirubin of 46 days (range: 0-551 days). One patient was rechallenged with He Shou Wu and two developed autoimmune features. One patient died of liver failure and three had chronic persistent liver injury. Conclusions The main clinicopathological injury pattern of He Shou Wu-induced liver injury is moderate to severe hepatitis with or without cholestasis. Most patients recover completely; however, chronic disease and death do occur.

BACKGROUND AND AIM Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naive, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (

Aim Previous studies have reported that hepatitis B virus (HBV) genotype is not a predictor of treatment response with nucleos(t)ide analog therapy. However, the impact of subgenotype on treatment response is unknown. The aim of this study is to identify the effect of HBV subgenotype on treatment response. Methods In this retrospective study, the derivation dataset comprised patients from the EFFORT study (NCT00962533) telbivudine monotherapy group; patients infected with genotypes B or C from the GLOBE (NCT00057265) and 015 (NCT00131742) studies formed the validation dataset. The HBV subgenotypes were determined using phylogenetic analysis based on the surface or overlapping polymerase gene. Molecular modeling was used to investigate relationships between positions of the substitutions within reverse transcriptase and genotypic resistance. Results Of the patients in the derivation dataset, 110, 24, 162, and 1 patients were classified as having HBV subgenotypes B2, C1, C2, or other, respectively, compared to 222, 146, 282, and 51 in the validation dataset, respectively. Patients infected with subgenotype C1 showed a higher virologic response rate and hepatitis B envelope antigen seroconversion rate, and lower genotypic resistance rate than those infected with subgenotypes B2 and C2. Patients with genotypic resistance to telbivudine with subgenotype C1 showed fewer secondary mutations. The crystal structure model of reverse transcriptase showed that these secondary mutations were located around the YMDD motif, which possibly influenced the chance of mutations at rtM204. Conclusion Hepatitis B virus subgenotype C1 is associated with better antiviral response to nucleoside analogs in hepatitis B envelope antigen-positive patients than B2 and C2 subgenotypes. The exact mechanism needs to be explored further.

Background and Aim Chronic hepatitis C virus (HCV) infection is the leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. In China, it is a major national health problem that demands nationwide coordinated emphasis on prevention and treatment. To inform these initiatives, a nationwide survey was conducted from January to April 2015 to evaluate the knowledge, awareness, and perceived obstacles to HCV care. Methods A sample of 1000 HCV specialists across mainland China were recruited. Respondents were asked a series of 30 open-ended single or multiple response and Likert-scale questions about their HCV treatment knowledge, experience, assessment of HCV care status in China, and perceptions about treatment barriers. Results Sixty percent of the respondents answered incorrectly to more than half of the questions on basic HCV treatment principles. Over half of them incorrectly believed that maintenance therapy should be prescribed for non-responders (72%) and longer treatment duration improved sustained viral response rates (62%), regardless of HCV RNA level changes. Sixty-six percent of them believed that HCV treatment would still be interferon-based therapy in the next 5 years in China. Patient-related barriers, in particular lack of disease awareness, were considered to be the most significant barriers to HCV care. Payer and medical-provider barriers included affordability issues, lack of reimbursement coverage for testing and treatments, and lack of referral to HCV specialists. Conclusions Focused and intense patient and provider education should be carried out to increase awareness. More effective direct-acting antivirals should be made available and affordable in China.

Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once-daily plus asunaprevir 100 mg soft capsules twice-daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment Week 24 (SVR24). Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on-treatment; none were considered related to study drugs. Two patients (1.3%) discontinued due to adverse events. Treatment was generally well-tolerated regardless of cirrhosis status. Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan. This article is protected by copyright. All rights reserved.

Universal HBV vaccination in infants has led to a dramatic decline of HBsAg prevalence in many parts of the world, but the positive rate of HBsAg in women of childbearing age is still high in endemic areas. Antiviral therapy during pregnancy may be indicated to control the liver disease of the mother or to prevent the MTCT. The decision on initiation, switching, continuation or stopage of the antiviral therapy should be made after careful consideration of the benefit and risk to both mothers and foetuses. For prepregnant women of childbearing age, a finite course of interferon is preferred if a pregnancy in the distant future is planned, whereas safer NAs could be started if a pregnancy in the near future is desired. For those who already started therapy with interferon or NAs before pregnancy, the switch to safer NAs is preferred. For women with newly diagnosed or with flare of CHB during pregnancy, category B NAs may be taken to treat their liver disease. For pregnant women with serum HBV DNA >10(6-7) IU/ml, safer NAs could be started in the third trimester to further the reduce MTCT rate.

Autoimmune hepatitis (AIH) is an inflammatory liver disease with diverse clinical spectrum, which predominantly affects females. This review provides detailed comparisons of epidemiology, genetic predispositions, clinical features, risk factors of hepatocellular carcinoma, and mortality in AIH patients between eastern and western countries. AIH prevalence and incidence are lower in Asia-Pacific area than in Europe and America. European and American patients seem to have more severe disease, characterized with human leukocyte antigen-DR3 haplotype, younger age, more AIH-induced "cirrhosis" at diagnosis, higher elevated serum immunoglobulin G levels, and positive rate of antisoluble liver antigen/liver pancreatitis. The overall AIH diagnostic accuracy of revised original criteria and simplified scoring system are similar in European/American populations and Asian. Cirrhosis at presentation and non-response to immunosuppressive therapy within 1 year are the most important predictors for poor prognosis of AIH patients.

Transforming growth factor-β1 (TGF-β1) induces hepatic progenitors to tumor initiating cells through epithelial-mesenchymal transition (EMT), thus raising an important drawback for stem cell-based therapy. How to block and reverse TGF-β1-induced transition is crucial for progenitors' clinical application and carcinogenic prevention. Rat adult hepatic progenitors, hepatic oval cells, experienced E-cadherin to N-cadherin switch and changed to α-smooth muscle actin (α-SMA) positive cells after TGF-β1 incubation, indicating EMT. When TGF-β1 plus EGF were co-administrated to these cells, EGF dose-dependently suppressed the cadherin switch and α-SMA expression. Interestingly, if EGF was applied to TGF-β1-pretreated cells, the cells that have experienced EMT could return to their epithelial phenotype. Abruption of EGF receptor revealed that EGF exerted its blockage and reversal effects through phosphorylation of ERK1/2 and Akt. These findings suggest an important attribute of EGF on opposing and reversing TGF-β1 effects, indicating the plasticity of hepatic progenitors.

Background and Aim Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). Methods Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 105 copies/mL, alanine aminotransferase 1.3–10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. Results At week 104, more patients in COMBO and OPTIMIZE groups achieved HBV-DNA

A high rate of chronic hepatitis B virus (HBV) infection in China is mainly caused by perinatal or early childhood transmission. Administration of universal HBV vaccination in infants has led to a dramatic decrease in HBV epidemiology, with hepatitis B surface antigen (HBsAg) prevalence declining from 9.75% in 1992 to 7.18% in 2006. The major HBV genotypes are B and C, with B being more prevalent in the southern part and C more prevalent in the northern part of China. A national survey carried out in 1992 showed that the hepatitis C virus (HCV) infection rate was 3.20% in general population in China. After implementation of mandatory HCV screening for blood transfusion and other precautions to prevent blood-borne disease since 1993, the new cases of HCV infection associated with blood or blood product has become very rare. Although the anti-HCV prevalence would be much higher in high-risk groups, a survey carried in 2006 showed that the anti-HCV prevalence rate was only 0.43% in general population. This sharp decline in HCV infection rate was mainly due to stringent administration and monitoring of blood donors and blood products, but may also be related to the remarkably improved specificity of anti-HCV test. The predominant HCV genotype in China is genotype 1b (60–70%), and the host interleukin-28b rs12979860 CC genotype is very frequent in Chinese population (over 80%).

Chronic hepatitis B infection is an important cause of liver-related mortality in China. This study assessed the efficacy and safety of entecavir in a heterogeneous patient population from a ‘real-world’ clinical practice setting in China. This prospective, observational cohort provides 48-week data on 2600 patients from 50 sites in China who received entecavir (0.5 or 1.0 mg) and were assessed for virologic, serologic and biochemical responses. Patients were nucleos(t)ide-na€ive or -experienced and had compensated or decompensated liver function. At Week 48, 1545/2424 (64%) patients with compensated liver disease and 30/44 (68%) patients with decompensated liver disease achieved HBV DNA

Telbivudine, one of the oral anti-hepatitis B virus (HBV) nucleoside analogues, has been used for more than 5 years to treat HBeAg-positive and -negative chronic hepatitis B (CHB) patients. This includes not only global Phase II and III trials, but also Chinese Phase III trials and several real-world clinical practice studies from China. The present review will first focus on 1-, 2- and 3-year data of telbivudine therapy on HBV DNA suppression, alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroconversion, viral resistance and safety in HBeAg-positive and -negative CHB patients. Second, telbivudine treatment predictors, including HBV DNA undetectability, ALT level and other immune-related markers at 12 and 24 weeks will be summarized to optimize therapy. Besides several retrospective studies, the Chinese EFFORT prospective study adapted from telbivudine virological response at 24 weeks has shown very promising results. Finally, the Chinese experience of using telbivudine in the second and third trimesters of pregnancy to prevent perinatal transmission of HBV infection will be touched on citing the latest studies.

Chronic hepatitis B (CHB) is a worldwide public health problem which represents an enormous economic and social burden. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Therefore, sustained suppression of HBV replication is the cornerstone for preventing the progression of disease and prolonging survival in patients with CHB. Pivotal clinical trials and real-world studies show that nucleos(t)ide analogues (NAs) are potent suppressors of HBV DNA replication with very good safety profiles. Although 1-year treatment with NAs only results in a modest rate of HBeAg seroconversion, extended treatment could increase this rate. Profound suppression of HBV DNA can result in histological improvement and a clinical benefit with a decrease in disease progression in patients with compensated or decompensated cirrhosis. Treatment must be begun with a highly potent and low resistant regimen to obtain long-term suppression of viral replication. An alternative solution may be a roadmap approach in which an inexpensive antiviral drug is started and another drug is added-on or switched-to if there is a suboptimal on-treatment decrease in HBV DNA. Clinical evidence has shown that once HBV DNA is suppressed and long-term HBeAg seroconversion is achieved, NAs can be stopped. In summary, high antiviral efficacy, excellent tolerance, extensive applicability, clearly proven histological improvement and long-term clinical benefit all make NAs the preferred choice for the management of CHB in most patients.

AIM To compare the immunogenicity of two modified hepatitis B virus (HBV) vaccination schedules in liver transplant recipients. Hepatitis B immunoglobulin (HBIG) in combination with nucleoside/nucleotide analogs (NUCs) is the recommended prophylaxis for preventing HBV recurrence following liver transplantation (LT). However, HBIG treatment is expensive. Active immunization with hepatitis B vaccine would be a preferable alternative prophylaxis to replace HBIG treatment. However, the overall response rate to standard vaccination (given at months 0, 1 and 6) is relatively low in immune-compromised patients. METHODS Two cohorts of 114 subjects were immunized with recombinant HBV vaccine containing S-antigen. The patients in the rapid schedule group were immunized with 40 μg HBV vaccine at months 0, 1, 2 and 3, and with 20 μg at months 4, 5 and 6. The patients in the accelerated schedule group were immunized with 40 μg of HBV vaccine at days 0, 7, 14 and 28, and 20 μg at months 2, 3 and 4. RESULTS The overall response rate was 16.7% (19/114) and all responders discontinued HBIG injection and only one patient developed HBV recurrence. The response rate was 24.6% (14/57) and 8.8% (5/57) in the rapid vaccination and the accelerated vaccination schedules, respectively (P = 0.024). CONCLUSION HBV vaccination may induce endogenous anti-HBs to replace HBIG in selected patients. Vaccination schedules may influence vaccine response, and individual optimization may improve response rate to HBV vaccination.

AIM To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro. METHODS Collagen type I were measured after LX-2 cell cultured with purified or serum HBV for 12, 24 and 48 h. Furthermore, evidence of HBV infection to LX-2 were detected, and different inhibitors were used to identify pathways regulating collagen I expression. RESULTS The 3 × 10(5) IU/mL purified/serum HBV increased collagen type I mRNA expression by 2.2-/3.2- and 1.3-/1.5-fold at 24 and 48 h, respectively. Collagen type I protein in the supernatant of purified/serum HBV group also increased compared to the control group (408.0 ± 8.0/384.4 ± 6.8 vs 262.7 ± 15.7 ng/mL, P

Aliment Pharmacol Ther 2011; 34: 424–431 Summary Background Previous studies suggested that a finite course of peginterferon alfa-2a may offer an alternative rescue therapy for patients with lamivudine resistance. However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion. Aim To explore the role of peginterferon alfa-2a, in the rescue treatment of HBeAg-positive chronic hepatitis B patients with lamivudine resistance. Methods In this randomised study, chronic hepatitis B patients with lamivudine resistance were treated with peginterferon alfa-2a for 48 weeks (n = 155) or adefovir for 72 weeks (n = 80). All enrolled patients were treated with lamivudine for the first 12 weeks. Results At 6 months posttreatment, 14.6% (18/123) of peginterferon alfa-2a-treated patients achieved HBeAg seroconversion, in contrast to 3.8% (3/80) of adefovir-treated patients after 72 weeks continuous therapy (P = 0.01). For peginterferon alfa-2a-treated patients, the rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log10 IU/mL from baseline at week 24, compared with patients with HBsAg decline ≤0.5 Log10 IU/mL from baseline at week 24 (25.5% vs. 7.7%, P = 0.01). After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA

Background: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB). Aims: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial. Methods: Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years. Results: Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial. Conclusions: Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.

Chronic hepatitis B virus (HBV) infection is a major health problem in the Asia-Pacific region. In the past decade, much progress has been made in the understanding and management of this disease. The introduction of universal vaccination has significantly reduced the incidence of perinatal infection in most Asia-Pacific countries. As the majority of the adult population have not been immunized at birth, we are still facing a large population of young HBV-infected patients in the coming two decades. The study of long-term longitudinal databases has provided deeper insight into the clinical significance of HBV DNA suppression, hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) seroclearance in chronic hepatitis B. With a better understanding on the natural history of HBV infection, one can now stratify the risk of chronic hepatitis B patients for adverse clinical outcomes and use this to individualize management. The introduction of non-invasive assessment of liver fibrosis can potentially reduce the necessity of liver biopsy. There have also been great advances in the development of antiviral therapy in the past decade. However, the high cost of HBV antiviral drugs poses major challenges to health authorities in many Asia-Pacific countries. Properly performed cost-effective analysis and understanding on the best timing of stopping antiviral drugs will be important to facilitate the most appropriate allocation of resources.

Background: Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials. Aims: The present phase IIIb, randomized, double-blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy. Methods: HBeAg-positive and HBeAg-negative adult patients (N=246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log10 copies/ml] under lamivudine treatment for 12–52 weeks were randomized (1:1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24. Results: The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (−1.9 ± 0.18 vs. −0.9 ± 0.27 log10 copies/ml; P 24 weeks of prior lamivudine treatment, all associated with pre-existent lamivudine-resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with

Background and Aim: N-methyl-4-isoleucine cyclosporine (NIM811), a new analogue of cyclosporine A, can inhibit collagen deposition in vitro and reduce liver necrosis in a bile-duct-ligation animal model. However, whether NIM811 effects on CCl4-induced rat liver fibrosis, and the related mechanism has not been determined. Methods: A liver fibrosis model was induced in Wistar rats using CCl4 for 6 weeks. Meanwhile, two different doses of NIM811 (low-dose 10 mg/kg and high-dose 20 mg/kg) were given to the CCl4-treated rats. Liver fibrosis was then evaluated according to histopathological scoring and liver hydroxyproline content. Serum alanine aminotransferase, aspartate aminotransferase and albumin levels, expression of matrix metalloproteinase-13, tissue inhibitor of metalloproteinase-1, α-smooth muscle actin and cyclophilin B and D in liver tissue were determined. Cyclophilin B and D were also studied in an hepatic stellate cell line. Results: Hydroxyproline content was decreased in both NIM811 groups compared with the model (P

Summary. Hepatitis B virus (HBV) infection has a high prevalence in China. Entecavir has shown superior efficacy over lamivudine in Chinese nucleoside-naive chronic hepatitis B (CHB) patients over 48 weeks, with continued clinical benefit to 96 weeks. The present study evaluates the long-term efficacy of entecavir in Chinese CHB patients who continued entecavir treatment for 144 weeks. Patients receiving either entecavir 0.5 mg/day (n = 258) or lamivudine 100 mg/day (n = 261) entered the initial 96-week randomized, double-blind, controlled efficacy study. Patients who did not achieve a consolidated response [HBV DNA

Hepatic stimulator substance (HSS) has been shown to protect liver cells from various toxins. However, the mechanism by which HSS protects hepatocytes remains unclear. In this study, we established BEL-7402 cells that stably express HSS and analyzed the protective ability of HSS on cells through mitochondrial permeability (MP). After administration of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a specific agent that leads to depolarization of the mitochondrial transmembrane potential, the apoptosis rate of HSS-expressing cells was significantly reduced, as measured using Hoechst staining and flow cytometry. The mitochondrial membrane transition and cytochrome c leakage were significantly inhibited in the HSS-expressing cells as compared with the untransfected cells, and, as a consequence, the cellular ATP content in the HSS-expressing cells was relatively preserved. Additionally, decreased caspase-3 activity was observed in the HSS-expressing cells treated with CCCP as compared with the vector-transfected cells and cells expressing mutant HSS. Furthermore, silencing of HSS expression using small interfering RNA accelerated CCCP-induced apoptosis. In isolated mitochondria, recombinant HSS reduced the release of cytochrome c induced by CCCP, indicating a possible role for HSS in regulation of mitochondrial permeability transition (MPT). HSS-expressing BEL-7402 cells are resistant to CCCP injury, and HSS protection is identical to that observed with cyclosporin A, an inhibitor of MPT. Therefore, we propose that the protective effect of HSS may be associated with blockade of MPT.

Pretreatment alanine transaminase (ALT) elevation may be used as a predictor for higher hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients. However, the role of dynamic changes of on-treatment ALT for seroconversion is unknown. A total of 170 naïve HBeAg-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogues (NA), either lamivudine, adefovir, entecavir, or telbivudine, for at least 2 years and followed up for 1 more year. Clinical characteristics were detected and analysed at baseline and at 3-month intervals. On-treatment ALT predicted HBeAg seroconversion more accurately than baseline ALT. Among the patients with on-treatment ALT/=1 x UNL, 1-/=2 x UNL, 2-/=5 x UNL and5 x UNL, HBeAg seroconversion was 11.4, 5.4, 24.4 and 65.0% (odds ratio = 1.0, 0.4, 2.5 and 14.4, respectively), respectively. Moreover, two models/types of seroconversion were observed. Type I was characterized by rapidly decreased ALT and HBV DNA during the first 3-month interval, but with high HBeAg reversion rate (50%) after consolidation treatment. Type II was a slow decreased DNA procedure accompanied by significant elevated ALT with less reversion (23%). Receiver operating characteristic curve analysis showed a 1.9-fold increased ALT ratio (present visit ALT: previous visit ALT) accompanied by at least a 0.8 log decreased HBV DNA may be used to classify these two seroconversion types. We conclude that on-treatment elevated ALT levels is a better predictor for seroconversion after NAs treatment, and HBV DNA profiles may help to identify different models of seroconversion.

De novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) always progresses to chronic hepatitis because of the patients' immunocompromised status, and only a few then acquire hepatitis B surface antigen (HBsAg) seroconversion even with efficient antiviral therapy. Here we reported the case of a liver transplant recipient with de novo HBV infection who had a favorable outcome after lamivudine (LAM) and adefovir dipivoxil (ADV) antiviral therapy. The patient received OLT because of end-stage primary biliary cirrhosis and was found to have de novo HBV infection 3 months later. She was treated with LAM, and her serum HBV DNA turned undetectable 2 weeks later. However, serum HBV DNA turned detectable again after 9 months of LAM therapy and a YMDD mutation was detected. The addition of ADV was efficient to treat LAM-resistant HBV. After 3 months of combination therapy, LAM was stopped and ADV monotherapy was continued. HBsAg seroconversion was achieved after an additional 12 months. The prevention and treatment of de novo HBV infection after OLT is discussed.

Background Hepatic oval cells, progenitor cells in the liver, can differentiate into hepatocytes and bile duct cells both in vitro and in vivo. Although hepatic stellate cells are another important cell component in the liver, less attention has been focused on the relationship between hepatic oval cells and hepatic stellate cells. Methods Hepatic oval cells were isolated from rats fed a choline-deficient diet supplemented with 0.1% ethionine for 6 weeks and characterized by electron microscopy, flow cytometry, reverse transcription polymerase chain reaction, Western blot and bi-direction differentiation. After treatment with transforming growth factor-beta1 (TGF-beta1), changes in cell viability, morphology, extracellular matrix (ECM) expression and immune phenotype were analysed in these cultured and adherent hepatic oval cells. Results The primary cultured hepatic oval cells were positive for the oval cell-specific markers OV-6, BD-1/BD-2 and M2PK as well as the hepatocyte markers albumin and alpha-foetoprotein. These hepatic oval cells differentiated bipotentially into hepatocytes or bile duct-like cells under appropriate conditions. It is noteworthy that these bipotential hepatic oval cells expressed ECM genes stably, including collagens, matrix metalloproteinases and tissue inhibitor of mellatoproteinase. Furthermore, except for growth inhibition and morphological changes in the hepatic oval cells after exposure to TGF-beta1, there was an increased expression of ECM genes, the onset expression of snail and loss expression of E-cadherin. During this process, TGF-beta1 treatment induced an upregulation of marker genes for hepatic stellate cells in hepatic oval cells, such as desmin and GFAP. Conclusion Except for the expression of ECM, the cultured hepatic oval cells could induce an increased expression of hepatic stellate cell markers by TGF-beta1 through an epithelial-mesenchymal transition process, which might indicate the contribution of hepatic oval cells to liver fibrosis.

Background/Aims: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). Method: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 μg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. Results: Differences (HBV vs HCV) were observed in the incidence of AEs (88–89 vs 96–100%), serious AEs (4–5 vs 7–16%) and treatment withdrawals (6–8 vs 17–33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P