Abstract
The full spectrum of risks for the life course of inactive hepatitis B virus (HBV) carriers remains unclear. In this study, 995 untreated HBV carriers (median age: 42.8 years; median ...follow‐up: 30.2 years) were included. Their data were sourced from a population‐based cohort study of male civil servants recruited in 1989–1992. Outcomes were identified by active follow‐up examinations and linkage with national health insurance research database. At baseline, 483 subjects were inactive carriers, 385 with indeterminate phase, and 127 with other phases. The joint lifetime risk for incident cirrhosis, decompensation, hepatocellular carcinoma, and liver‐related deaths was lower for inactive carriers compared to subjects in other phases (
p
< 0.0001). There was a trend of increase in incidence among inactive carriers; the 5‐, 10‐, and 20‐year cumulative incidences were 1.86%, 6.03%, and 10.07%, respectively. Of the inactive carriers, 37.7% cleared HBsAg and 36.6% had biochemical relapse during the study. Biochemical relapse, obesity, and advanced age were predictors for disease progression in inactive carriers. Virological relapse was the predominant cause of biochemical relapse. Higher HBV‐DNA levels (≥1000 copies/mL or 200 IU/mL) and HBV genotype B (vs. C) were associated with higher virological relapse rate. After 30 years, we found that one‐time measure of inactive carrier state continued to have the lowest risk compared with other infection phases. Despite a more favorable prognosis, inactive carriers had a non‐negligible risk. Our findings of lifetime risk may provide important clues for the management of such patients and consideration of therapeutic strategies aiming to achieve functional cure.
Background and Aim
The aim of this study was to assess the impact of body mass index (BMI) on the clinical and histological characteristics of patients with nonalcoholic fatty liver disease (NAFLD).
...Methods
Patients with clinically diagnosed NAFLD who received liver biopsy were retrospectively enrolled from 2007 to 2019. For comparison, all of the patients were divided into lean body mass (< 23 kg/m2), overweight (23–24.9 kg/m2), and obesity (BMI ≧ 25 kg/m2).
Results
A total of 572 patients with histologically confirmed NAFLD, including 40 (6.99%) lean body mass, 54 (9.44%) overweight, and 478 (83.57%) obese patients, were recruited. Obese NAFLD patients had significantly higher grade of steatosis (grade 3: 29.92% vs 22.22% vs 12.5%, P < 0.0001) and hepatocyte ballooning (grade 2: 14.85% vs 12.96% vs 12.5%, P < 0.0001) than overweight and lean NAFLD patients. The prevalence of nonalcoholic steatohepatitis (NASH) was 22.5%, 25.93%, and 36.19% in lean, overweight, and obese NAFLD patients, respectively. Obesity was significantly associated with fibrosis severity (P = 0.03). The fibrosis index based on four factors (FIB‐4) score can identify NAFLD patients without significant fibrosis or with cirrhosis. The areas under the receiver‐operating characteristic curve of FIB‐4 score to identify patients without significant fibrosis or with cirrhosis were 0.82 (95% confidence interval CI: 0.69–0.96) and 0.87 (95% CI: 0.76–0.99) in lean patients; 0.77 (95% CI: 0.61–0.93) and 0.81 (95% CI: 0.59–1.0) in overweight patients; and 0.77 (95% CI: 0.72–0.82) and 0.89 (95% CI: 0.85–0.92) in obese patients.
Conclusions
The majority of NAFLD patients are obese, as defined by BMI. Obesity was significantly associated with NASH and hepatic fibrosis severity in patients with NAFLD.
In the present study, we demonstrated that the prevalence of nonalcoholic steatohepatitis (NASH) was higher in obese NAFLD patients than in those with lean and overweight NAFLD. Histologically, obese NAFLD patients had significantly higher grade of steatosis and hepatocyte ballooning than lean and overweight NAFLD patients. Moreover, the fibrosis index based on four factors (FIB‐4) score had good values of area under receiver‐operating characteristic curves to identify NAFLD patients without significant fibrosis or with cirrhosis, irrespective the body mass index.
Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their ...impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis.
251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages.
In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67).
A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.
Both nuclear and cytoplasmic overexpression of metastatic tumor antigen 1 (MTA1) contributes to tumorigenesis of HCC. Most studies have focused on nuclear MTA1 whose function is mainly a chromatin ...modifier regulating the expression of various cancer-promoting genes. By contrast, the molecular mechanisms of cytoplasmic MTA1 in carcinogenesis remain elusive. Here, we reveal a role of MTA1 in posttranscriptional gene regulation.
We conducted the in vitro and in vivo RNA-protein interaction assays indicating that MTA1 could bind directly to the 3'-untranslated region of MYC RNA. Mutation at the first glycine of the conserved GXXG loop within a K-homology II domain-like structure in MTA1 (G78D) resulted in the loss of RNA-binding activity. We used gain- and loss-of-function strategy showing that MTA1, but not the G78D mutant, extended the half-life of MYC and protected it from the lethal -7-mediated degradation. The G78D mutant exhibited lower activity in promoting tumorigenesis than wild-type in vitro and in vivo. Furthermore, RNA-immunoprecipitation sequencing analysis demonstrated that MTA1 binds various oncogenesis-related mRNAs besides MYC . The clinical relevance of cytoplasmic MTA1 and its interaction with MYC were investigated using HBV-HCC cohorts with or without early recurrence. The results showed that higher cytoplasmic MTA1 level and MTA1- MYC interaction were associated with early recurrence.
MTA1 is a generic RNA-binding protein. Cytoplasmic MTA1 and its binding to MYC is associated with early recurrence in patients with HBV-HCC. This function enables it to regulate gene expression posttranscriptionally and contributes to hepatocarcinogenesis.
To identify the risk factors of oral cancer, we investigated the association between chronic hepatitis C (CHC) and oral cancer, and the development of oral cancer after anti‐hepatitis C virus (HCV) ...therapy. We conducted a nationwide, population‐based cohort study from 2004 to 2012 from the Taiwan National Health Insurance Research Database. CHC patients without anti‐HCV therapy were matched with those non‐HCV patients by age, sex and comorbidities. Moreover, CHC patients who underwent pegylated interferon and ribavirin (PegIFN/RBV) anti‐HCV therapy were matched with CHC patients without anti‐HCV therapy. A total of 100,058 patients were included in the HCV cohort and non‐HCV cohorts, respectively. Their mean age was 59 years and 50% of these were male. CHC infection significantly increased the cumulative incidence of lichen planus and oral cancer. After adjustment for confounders and competing mortality, CHC infection significantly increased the risk of oral cancer (hazard ratio HR: 1.677, 95% confidence interval CI: 1.392–2.020, p < 0.001). Another 23,735 CHC patients without anti‐HCV therapy were matched with 23,735 CHC patients in the treatment cohort. After adjustment for confounders and competing for mortality, the risk of oral cancer was significantly reduced in CHC patients receiving anti‐HCV therapy (HR: 0.652, 95% CI: 0.479–0.887, p = 0.007). To minimize the inclusion of pre‐existing unidentified oral cancer, we excluded oral cancer developed within the first year of CHC or anti‐HCV therapy and found these associations remained statistically significant. In conclusion, CHC significantly increases the risk of oral cancer. Moreover, PegIFN/RBV antiviral therapy significantly reduces the risk of HCV‐related oral cancer.
What's new?
The incidence of oral cancer is increasing worldwide, owing to diverse factors. One such factor may be hepatitis C virus (HCV) infection, which is associated with oral lichen planus, a premalignant lesion for oral cancer. Whether HCV is linked to oral cancer, however, remains uncertain. In this population‐based cohort study, chronic HCV infection was associated with a significant increase in oral cancer risk. This risk was reduced in patients receiving pegylated interferon‐based anti‐HCV therapy. The findings indicate that antiviral therapy protects against chronic HCV infection‐associated oral cancer and supports the idea that HCV contributes to development of the malignancy.
Chronic hepatitis B (CHB) exhibits a variety of clinical outcomes, ranging from spontaneous resolution of hepatitis B to severe adverse consequences, including the development of cirrhosis, hepatic ...failure, and hepatocellular carcinoma. The heterogeneous clinical courses of chronic hepatitis B virus (HBV) infection reflect the complex host–virus interactions, and point to the difficulty and necessity of identifying the patients at risk. With the advance of HBV virology, several viral factors have been found to be associated with the long-term clinical outcomes of CHB patients. Different viral factors probe different aspects of CHB. Integration of these viral factors may help to determine the disease state of patients more accurately, and identify the patients who require timely antiviral therapy to prevent the development of detrimental clinical outcomes. In this article, we will introduce the conventional and emerging viral factors that are associated with clinical outcomes and discuss their utility in a clinical setting.
Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother‐to‐infant transmission in highly viremic HBV‐infected women. Data on hepatitis B surface antigen (HBsAg) levels in ...pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV‐infected mothers with HBV DNA ≥7.5 log10 IU/ml were tested for HBsAg and HBV DNA from baseline to 6 months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1 month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32 ± 0.47 vs. 4.54 ± 0.35 log10 IU/ml, p = .0004) and markedly lower HBV DNA (4.26 ± 0.97 vs. 8.11 ± 0.70 log10 IU/ml, p < .0001) than the control group. In the TDF group, mean reduction of HBsAg and HBV DNA from baseline to delivery were 0.22 ± 0.38 and 3.96 ± 0.93 log10 IU/ml. HBsAg reduction had a positive correlation (r = .309; p = .0017) with HBV DNA reduction, and was predictive of HBV DNA reduction ≥3 log10 IU/ml (area under the receiver operating characteristic curve, 0.67; 95% confidence interval, 0.50–0.82). At 6 months postpartum, TDF and control group had comparable HBsAg and HBV DNA. In conclusion, HBsAg decreased slightly at delivery in pregnant women receiving TDF. For monitoring the effect of antiviral therapy during pregnancy, HBV DNA is a better marker than HBsAg. Our data provided valuable information regarding monitoring HBV‐infected pregnant women using antiviral therapy.
Background/aims
Direct‐acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)‐infected patients. The real‐world treatment outcome in Taiwanese patients on a ...nationwide basis is elusive.
Methods
The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end‐of‐treatment).
Results
A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype‐1 GT1, 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma HCC, 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment‐naïve noncirrhotic, treatment‐naïve cirrhotic, treatment‐experienced noncirrhotic and treatment‐experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment‐experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment‐naïve noncirrhotic patients (94.8%) and treatment‐experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio aOR/95% confidence interval CI: 117.1/52.4‐261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25‐14.9, P = .0003 and aOR/CI: 1.55/1.05‐2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57‐7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67‐3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94‐5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20‐5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57‐2.97, P < .001).
Conclusions
DAAs are highly effective in treating Taiwanese HCV patients in the real‐world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.
Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive ...biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis.
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