Xiaojuan Ou

New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment

Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir‐based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. Conclusion: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438‐1450)

Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B.

Background and Aims Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients. Methods The diagnostic performance of ten noninvasive models (HALF index, FibroScan, S index, Zeng model, Youyi model, Hui model, APAG, APRI, FIB-4 and FibroTest) was assessed against the liver histology by ROC curve analysis in CHB patients. The reproducibility of the ten models were evaluated by recalculating the diagnostic values at the given cut-off values defined by the original studies. Results Six models (HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest) had AUROCs higher than 0.70 in predicting any fibrosis stage and 2 of them had best diagnostic performance with AUROCs to predict F≥2, F≥3 and F4 being 0.83, 0.89 and 0.89 for HALF index, 0.82, 0.87 and 0.87 for FibroScan, respectively. Four models (HALF index, FibroScan, Zeng model and Youyi model) showed good diagnostic values at given cut-offs. Conclusions HALF index, FibroScan, Zeng model, Youyi model, S index and FibroTest show a good diagnostic performance and all of them, except S index and FibroTest, have good reproducibility for evaluating liver fibrosis in CHB patients. Registration Number ChiCTR-DCS-07000039.

Procoagulant imbalance aggravated with falling liver function reserve, but not associated with the presence of portal vein thrombosis in cirrhosis.

Objectives Hypercoagulability, hemodynamic changes, and endothelial injury are the three major contributors to the development of thrombosis. However, the role of hypercoagulability in portal vein thrombosis (PVT) in liver cirrhosis is still controversial. The aim of this study is to elucidate the relationship between procoagulant imbalance and PVT in patients with liver cirrhosis. Methods This study included 151 patients with cirrhosis with (n=20) or without PVT (n=131). Levels of procoagulant factor (FVIII) and anticoagulants [protein C (PC), protein S (PS), and antithrombin (AT)] were measured. Procoagulant imbalance was also evaluated using a thrombin generation test with/without Protac and the results were expressed as Protac-induced coagulation inhibition percentage (PICI%). The lower the PICI% value, the greater the procoagulant imbalance. Results The levels of PC (P<0.001), PS (P<0.05), and AT (P<0.001) decreased progressively from Child–Pugh A to C in all patients, whereas the levels of FVIII did not alter with the severity of cirrhosis (P>0.05), which indicated the balance tilting toward procoagulation in liver cirrhosis. Similarly, the PICI% values decreased from Child–Pugh A to C (P<0.001). However, there were no differences in the levels of PC, PS, AT, FVIII or PICI% between patients with and without PVT (P>0.05), even after stratification by Child–Pugh classification (P>0.05). Conclusion Procoagulant imbalance is not associated with the presence of PVT in patients with cirrhosis, although the imbalance worsens with the severity of cirrhosis.

An Analysis of Immunoreactive Signatures in Early Stage Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is prevalent worldwide and early diagnosis of HCC is critical for effective treatment and optimal prognosis. Methods Serum was screened first by immunoproteomic analysis for HCC-related tumor associated antigens (TAAs). Selected TAAs were clinically evaluated retrospectively in patients with HCC, liver cirrhosis, chronic hepatitis and healthy controls. Levels of autoantibody to the selected TAAs were measured by protein microarrays containing protein antigens of the candidate TAAs. Analyses were done by using receiver operating characteristics (ROC) to calculate diagnostic accuracy. Findings Twenty-two candidate TAAs were assessed by protein microarray analysis in 914 participants with serum α-fetoprotein (AFP) available. Twelve candidate TAAs were statistically different in signal intensity between HCC and controls. Among them, CENPF, HSP60 and IMP-2 showed AUC (area under the curve) values of 0.826, 0.764 and 0.796 respectively for early HCC. The highest prevalence of autoantibody positivity was observed in HCC cases with BCLC tumor stage A, well-differentiated histology and Child-Pugh grade C. Specifically, 73.6% or 79.3% cases of early HCC with negative AFP were positive for autoantibody to CENPF or HSP60. Interpretation Tumor-associated autoimmune reactions may be triggered by early stage HCCs. Measurement of serum autoantibody to TAAs may be complementary to AFP measurements and improve diagnosis of early HCC.

Female gender lost protective effect against disease progression in elderly patients with chronic hepatitis B

Female gender and younger age are protective factors against disease progression in chronic hepatitis B (CHB). However, it is not clear whether the disease progression still remains slow in elderly females. This study investigated the interaction of female gender and older age on the development of cirrhosis in patients recorded in China Registry of Hepatitis B. A total of 17,809 CHB patients were enrolled in this multi-center cross-sectional study. The prevalence of cirrhosis in female CHB patients increased faster than that in male CHB patients over 50 years old. Multivariate analysis showed that the increase of adjusted ORs for developing cirrhosis in females started to accelerate after 50 years old: 11.19 (95% CI: 5.93–21.11) in women versus 14.75 (95% CI: 8.35–26.07) in men at ages of 50–59 years, 21.67 (95% CI: 11.05–42.47) versus 24.4 (95% CI: 13.00–45.80) at ages 60–69 years, and 18.78 (95% CI: 6.61–53.36) versus 12.09 (95% CI: 4.35–33.61) in those over 70 years. In conclusion, the protective effect of female gender against cirrhosis gradually lost with increasing age, therefore disease progression should be monitored more closely in elderly women with CHB.

Different models of HBeAg seroconversion predicated by on-treatment ALT and HBV DNA profiles

Summary.  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 × UNL, 1–≤2 × UNL, 2–≤5 × UNL and >5 × 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.

Two patterns of alanine aminotransferase increase to predict long-term viral response in chronic hepatitis B patients: virus- or host-induced?

BACKGROUND Serum alanine aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hepatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes. METHODS A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval. RESULTS Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-γ-expressing T-helper cells were increased in patients with host-induced ALT increases. CONCLUSIONS Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes.

On-treatment changes of liver stiffness at week 26 could predict 2-year clinical outcomes in HBV-related compensated cirrhosis

It is unclear whether liver stiffness measurement (LSM) dynamic changes after anti‐HBV treatment could predict the risk of liver‐related events (LREs), particularly in patients with HBV‐related compensated cirrhosis.

Effective viral suppression is necessary to reduce hepatocellular carcinoma development in cirrhotic patients with chronic hepatitis B: Results of a 10-year follow up

Abstract High viral load is an independent risk factor for development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Antiviral therapy can reduce but not eliminate the risk of HCC. The aim of this study was to identify the risk factors for HCC development in CHB patients during antiviral therapy. CHB patients with HBV DNA level ≥104 copies/mL, with or without compensated cirrhosis receiving adefovir were followed up every 6 months for 10 years (2004–2014). The primary endpoint was the development of HCC. The cumulative incidence and risk factors of HCC were evaluated by the Kaplan-Meier method and multivariate Cox proportional hazards models. At baseline, 28 of the 120 patients (23.3%) were cirrhotic. One patient developed HCC within 1 year, and therefore 119 patients were analyzed. At the end-point of follow-up, 59.7% (71/119) patients achieved virological remission (VR). Overall, 16 patients developed HCC, giving a 10-year cumulative incidence of 15.73%. Multivariate analysis showed that cirrhosis at baseline and failure to achieve VR were significant risk factors for HCC. The 10-year incidence of HCC was significantly higher in cirrhotic than noncirrhotic patients (43.16% vs. 7.05%, P < .0001). For cirrhotic patients, the 10-year incidence of HCC was significantly higher in patients without VR than those with VR (62.24% vs. 27.78%, P = .0139). Cirrhosis at baseline and failure to achieve VR during antiviral therapy were significant risk factors for HCC development in CHB patients. Effective viral suppression is necessary to reduce HCC development in cirrhotic CHB patients.

Hepatitis B virus directly promotes collagen I expression of LX-2 cells without infection in vitro.

Aim:  To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro.