Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Unsatisfying antiviral therapeutic effect in patients with mother-to-child transmissed chronic hepatitis B virus infection: a prospective multi-center clinical study.

BACKGROUND: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. METHODS: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. RESULTS: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. CONCLUSION: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. TRIAL REGISTRATION: NCT01962155; https://clinicaltrials.gov.

Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: A randomized controlled trial.

Mortality from hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV-related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV-related ACLF were enrolled in this open-label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 105 cells/kg allogeneic bone marrow-derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%-84.8%) versus 55.6% (95% confidence interval 42.3%-68.9%) for the SMT group (P = 0.03). There were no infusion-related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5-24 of follow-up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow-derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End-Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). CONCLUSION: Peripheral infusion of allogeneic bone marrow-derived MSCs is safe and convenient for patients with HBV-related ACLF and significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209-219).

Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases.

Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase (AST) to platelet ratio index (APRI) and FIB-4 score for significant fibrosis. In conclusion, CXCL-11 was independently associated with at least moderate inflammation, whereas IL-2R and TGF-α were independent indicators of significant fibrosis in both, total CHB patients and patients with normal or mildly elevated ALT. An IL-2R and TGF-α based score (fib-index) was superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with normal or mildly elevated ALT.

[Therapeutic effects of Fuzhenghuayu decoction in a CCl4-induced liver cirrhosis rat model and on hepatic stellate cell activation].

OBJECTIVE: To evaluate the influence of Fuzhenghuayu decoction on fibrotic liver tissue and activated hepatic stellate cells (HSCs) using a carbon tetrachloride (CCl4)-induced liver cirrhosis rat model system. METHODS: Sixty-four Sprague-Dawley rats were randomly divided into the following groups: normal (non-model, non-drug intervention), CCl4 liver fibrosis model, and CCl4 liver fibrosis model Fuzhenghuayu drug intervention at low dose (0.75 g/kg/d) and high dose (1.5 g/kg/d). The drug intervention was administered via oral-gastric irrigation once daily for 6 times per week over a 6-week period. Four rats from each group were sacrificed at the end of week 2, 4, and 6 for serum and liver tissue collection. Liver fibrosis was evaluated by histology, and expression of a-smooth muscle actin (a-SMA) was determined by immunohistochemistry. Liver function was assessed by measuring levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil). Between-group comparisons were made by completely random design and ANOVA with Bonferroni correction. RESULTS: At the end of weeks 2, 4 and 6, all four groups showed significantly different levels of ALT, AST, and TBil; in addition, the model group and drug intervention groups had significantly higher levels of ALT, AST, and TBil than the control group, the drug intervention groups showed significantly lower levels of ALT, AST, and TBil than the model group (P less than 0.01 or less than 0.05), and the differences between the low dose and high dose groups reached statistical significance (P less than 0.01 or less than 0.05). At the end of weeks 2, 4 and 6, the model group and drug intervention groups had significantly higher area ratio of liver fibrosis than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but the two drug intervention groups had significantly less area ratio of liver fibrosis than the model group (P less than 0.05) and the high dose group showed the most robust decrease. In addition, the model group and drug intervention groups showed higher expression of a-SMA than the normal group (F = model: 18.68, low dose: 49.95, high dose: 82.44, P less than 0.01), but two drug intervention groups had significantly less a-SMA than the model group (F = model: 46.32, low dose: 40.30, high dose: 58.42, P less than 0.05) and the high dose group showed the most robust decrease. CONCLUSION: The Fuzhenghuayu decoction reduces the numbers of activated HSCs, thereby leading to down-regulated a-SMA expression and reduced degree of liver fibrosis; these effects may represent the mechanism by which this drug suppresses hepatic fibrosis.

Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure.

Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF). The major acute-phase mediators associated with FHF, including IL-1ß, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs) have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra) plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1ß, IL-6), and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

Development of a sensitive prognostic scoring system for the evaluation of severity of acute-on-chronic hepatitis B liver failure: a retrospective cohort study.

PURPOSE: The purpose of the current study was to establish an objective, simple, and sensitive prognostic scoring system for estimating the severity of acute-on-chronic liver failure in hepatitis B (ACLFB). METHODS: A novel prognostic scoring system was calculated from six clinical indices including total bilirubin (TB), prothrombin activity (PTA), creatinine (Cr), hepatic encephalopathy (HE), infections, and the depth of ascites from 726 patients with ACLFB. Indices were scored from 1 to 4 according to their severity. Groups of the same patients were scored with three-indices (TB, PTA and Cr), four-indices (TB, PTA, Cr and HE), five-indices (TB, PTA, Cr, HE and the depth of ascites) or six-indices (TB, PTA, Cr, HE, the depth of ascites, and infections). The differences in the sensitivity and specificity of four scoring systems were analyzed. RESULTS: The demarcation points of the three-, four-, five- and six-indices scoring systems were 4.62, 6.12, 7.88 and 9.57, respectively. The analysis of the areas under the receiver operating characteristic (ROC) curve indicated that the four-, five- and six-indices scoring systems were more exact, and objective than the three-indices prognostic scoring system. In the six-indices scoring system, the survival rates of patients with scores from 2 to 6 was 98.31% (233/237), and the mortality rate of patients with scores of 16 and above was 100.00% (140/140), while the mortality rates were 8.33% (3/36) and 96.43% (27/28) for those with scores from 7 to 15, respectively. CONCLUSION: A six-indices scoring system is an objective, pertinent, and sensitive system, and may be useful for the prognostic evaluation of ACLFB.

A Novel prognostic scoring system to predict 3-month mortality risk in patients with acute-on-chronic liver failure in hepatitis B: a retrospective cohort study.

PURPOSE: The present study was done to establish an objective, sensitive prognostic scoring system and to determine the applicability of this model in predicting the 3-month mortality of patients with acute-on-chronic liver failure in hepatitis B (ACLFB). METHODS: We developed a novel prognostic scoring system, calculated from six clinical indices including serum total bilirubin, prothrombin activity, serum creatinine, hepatic encephalopathy, infections, and the depth of ascites from 499 patients with ACLFB. Differences in the sensitivity, specificity, and practicality of a Novel prognostic scoring system and the model of end-stage liver disease (MELD) were analyzed. RESULTS: The areas under the receiver operating characteristic curve (ROC) for the Novel scoring systems and MELD scoring systems were 0.967 (95% CI, 0.956-0.977) and 0.900 (95% CI, 0.878-0.922), respectively. The analysis of the ROC curve indicated that the Novel scoring systems were an exact, pertinent, and objective prognostic model with greater accuracy than the MELD. In the Novel scoring systems, the survival rate of these patients whose scores ranged from 2 to 6 was 98.80%, while for those whose scores point at 7 and 15, the mortality rates were 8.70% (2/23) and 95.45% (21/22), respectively, and the mortality rate of these patients whose scores were 16 and above was 100.00%. However, in the MELD prognostic scoring systems, there were no score ranges with 100.00% survival rate. CONCLUSIONS: We developed an objective, pertinent, and sensitive prognostic scoring system that predicted the 3-month mortality of patients with ACLFB with greater accuracy than the MELD.

Collagen proportionate area of liver tissue determined by digital image analysis in patients with HBV-related decompensated cirrhosis.

BACKGROUND: The accurate assessment of the degree of hepatic fibrosis plays a critical role in guiding the diagnosis, treatment and prognostic assessment of chronic liver diseases. Liver biopsy is currently the most reliable method to evaluate the severity of hepatic fibrosis. However, liver biopsy is an invasive procedure associated with morbidity and mortality, and has several limitations in patients with decompensated cirrhosis. There is no report on the collagen proportionate area (CPA) of liver tissue in the decompensated stage of cirrhosis. This study aimed to determine the CPA of resected liver tissue samples from patients with HBV-related decompensated cirrhosis using digital image analysis, and to analyze the relationship between the CPA and liver functional reserve. METHODS: Fifty-three resected liver tissue samples from liver transplant patients with chronic hepatitis B-induced decompensated cirrhosis were stained with Masson's trichrome, and the CPA in these samples was quantitatively determined using digital image analysis. The values of relevant liver function just before liver transplantation, the CPA in liver tissue, and their correlation were analyzed. RESULTS: The mean CPA at the decompensated stage of cirrhosis was 35.93+/-14.42% (11.24%-63.41%). The correlation coefficients of the CPA with a model for end-stage liver disease score, serum total bilirubin and international standard ratio of prothrombin B were 0.553, 0.519 and 0.533, respectively (P<0.001). With increasing CPA values, the three indices reflecting liver functional reserve also changed significantly. CONCLUSIONS: The degree of fibrosis may be correlated with the functional reserve. With the advancement of fibrosis, the liver functional reserve is attenuated accordingly.

Prevention and risk factors of the HBV recurrence after orthotopic liver transplantation: 160 cases follow-up study.

BACKGROUND: The aim of this study was to analyze the combination with long-term, low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogs as prophylaxis for hepatitis B virus (HBV) recurrence and to assess the risk factors of HBV recurrence after orthotopic liver transplantation (OLT). METHODS: One hundred sixty patients undergoing OLT with HBV-related liver disease make up the cohort studied. Long-term, low dosage of HBIG in combination with nucleos(t)ide analogs were used as prophylaxis for HBV recurrence after OLT. Patient preoperative data were collected by a retrospective method, and the rate and risk factors of HBV recurrence post-OLT after a long-term follow-up were analyzed. RESULTS: Nineteen patients developed hepatitis B recurrence for a rate of recurrence of 11.88% (19/160). There was no significant correlation between HBV recurrence after OLT and the level of HBV DNA, HBeAg state pre-OLT, or the use of nucleoside analog drug therapy pre-OLT (P>0.05). Of 19 patients with HBV recurrence, 17 patients used Lamivudine, and HBV YMDD mutants were detected in nine cases. The HBV-YMDD mutation was the major reason for recurrence of HBV in our study (P<0.001). CONCLUSIONS: Long-term use of combination prophylaxis with nucleoside analogs and low-dose HBIG can effectively prevent hepatitis B recurrence after OLT, and that a positive preoperative serum HBV DNA status did not affect the recurrence rate of HBV post-OLT. Preoperative nucleoside analogs therapy is unlikely to be obligatory if the patients received effective combination prophylaxis postoperatively. HBV YMDD mutation is the primary reason for HBV recurrence in patients treated with Lamivudine after OLT.

Effect of revaccination using different schemes among adults with low or undetectable anti-HBs titers after hepatitis B virus vaccination.

Our objective was to investigate the effect of various reimmunization schemes for hepatitis B in adults with low or undetectable anti-HBs titers. Over 2 years, 10 µg of Saccharomyces cerevisiae-recombinant hepatitis B virus (HBV) vaccine (synthesized in China) was used in at least one standardized scheme to immunize 2,310 healthy male and nonpregnant female adults. Of these, 240 subjects tested negative for hepatitis B markers. These 240 subjects were equally divided into 4 groups. The first group, designated Engerix-40, was revaccinated with 40 µg Engerix-B; the second, Engerix-20, was revaccinated with 20 µg Engerix-B; the third, Chinese-20, was revaccinated with 20 µg Chinese-made yeast-recombinant vaccine; and the last group, Chinese-10, was revaccinated with 10 µg Chinese-made yeast-recombinant vaccine. Blood samples were collected before and 1, 2, 8, and 12 months after the first injection. The anti-HBs-positive conversion rates of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than that of the Chinese-10 group (P < 0.01). Over time, the anti-HBs conversion rate increased in all groups, but values were significantly different from those for the other groups only in the Chinese-10 group (P < 0.001). The anti-HBs geometric mean titers (GMTs) of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than in the Chinese-10 group (P < 0.05). Increased doses raise and maintain anti-HBs titers in subjects with low or undetectable titers after HBV vaccination.

[Association between the serum HBV DNA loads normalized to hepatic parenchyma cell volume and the liver histopathologic inflammation gradings in the immune clearance phase].

OBJECTIVE: To investigate the relationship between the serum HBV DNA loads normalized to hepatic parenchyma cell volume and the liver histopathologic inflammation gradings in the immune clearance phase during the natural history of hepatitis B. METHODS: Serum HBV DNA loads were detected by fluorescence polymerase chain reaction and normalized to hepatic parenchyma cell volume. The association between normalized HBV DNA loads and liver inflammation histopathologic grade were analyzed. RESULTS: The serum HBV DNA loads in patients with liver inflammation histopathologic grading 1, 2, 3 and 4 were 8.20*10(5)+/-9.11*10, 1.36*10(6)+/-5.96*10, 8.12*10(5)+/-8.01*10 and 2.08*10(6)+/-3.69*10 copies/ml, respectively (P more than 0.05). But the serum HBV DNA loads normalized to hepatic parenchyma cell volume in their located fibrosis stage were 9.24*10(8)+/-935, 5.33*10(9)+/-756, 1.06*10(10)+/-1770 and 3.31*10(11)+/-518 copies/ml, respectively (P less than 0.05). CONCLUSION: The serum HBV DNA load normalized to hepatic parenchyma cell volume in patients with different fibrosis stages is associated with liver histopathologic inflammation gradings.

Decline of serum HBV DNA and no change apportioned by the same hepatic parenchyma cell volume from hepatic fibrosis stage 1 to stage 4 during the natural history of chronic hepatitis B.

During the initial phase of chronic hepatitis B virus (HBV) infection, serum HBV DNA levels are high. Contrarily, fibrosis, cirrhosis and hepatocellular carcinoma have been found in patients with lower serum HBV DNA levels. The aim of this study is to clarify HBV DNA level dynamics of serum apportioned by the same hepatic parenchyma cell volume (HPCV) in hepatic fibrosis stages 1-4 during the natural history of chronic hepatitis B. Serum HBV DNA levels were evaluated by real-time polymerase chain reaction. Further, serum HBV DNA levels were apportioned by and compared with the same HPCV in hepatic fibrosis stages 1-4, respectively. Serum HBV DNA levels were 8.91 x 10(6) +/- 4.37 x 10(1), 8.13 x 10(6) +/- 7.41 x 10(1), 9.55 x 10(5) +/- 1.02 x 10(2), and 4.07 x 10(5) +/- 7.24 x 10(1) copies/ml, respectively; there were differences among hepatic fibrosis stages 1-4 (p < 0.021-0.000). However, serum HBV DNA levels apportioned by the same volume of hepatic parenchyma cells in hepatic fibrosis stages 1-4 were 3.47 x 10(10) +/- 8.71 x 10(2), 1.02 x 10(11) +/- 9.55 x 10(2), 1.41 x 10(10) +/- 2.57 x 10(3), and 3.72 x 10(10) +/- 3.02 x 10(3) with HPCV proportions 65.9, 62.7, 58.9, and 53.3%, respectively; there were no differences among hepatic fibrosis stages 1-4 (p > 0.203-0.967).Following the progression of hepatic fibrosis from stage 1 to 4, ongoing decline of HPCV is responsible for a declining trend of serum HBV DNA levels.

Liver fibrosis in chronic viral hepatitis: an ultrasonographic study.

AIM: To select valuable ultrasonographic predictors for the evaluation of hepatic inflammation and fibrosis degree in chronic hepatitis, and to study the value of ultrasonography in the evaluation of liver fibrosis and compensated liver cirrhosis in comparison with serology and histology. METHODS: Forty-four ultrasonographic variables were analyzed and screened using color Doppler ultrasound system in 225 patients with chronic viral hepatitis and compensated liver cirrhosis. The valuable ultrasonographic predictors were selected on the basis of a comparison with histopathological findings. The value of ultrasonography and serology in the evaluation of liver fibrosis degree and the diagnosis of compensated liver cirrhosis was also studied and compared. Meanwhile, the influencing factors on ultrasonographic diagnosis of compensated liver cirrhosis were also analyzed. RESULTS: By statistical analysis, the maximum velocity of portal vein and the degree of gall-bladder wall smoothness were selected as the valuable predictors for the inflammation grade (G), while liver surface, hepatic parenchymal echo pattern, and the wall thickness of gall-bladder were selected as the valuable predictors for the fibrosis stage (S). Three S-related independent ultrasonographyic predictors and three routine serum fibrosis markers (HA, HPCIII and CIV) were used to discriminate variables for the comparison of ultrasonography with serology. The diagnostic accuracy of ultrasonography in moderate fibrosis was higher than that of serology (P<0.01), while there were no significant differences in the general diagnostic accuracy of fibrosis as well as between mild and severe fibrosis (P<0.05). There were no significant differences between ultrasonography and serology in the diagnosis of compensated liver cirrhosis. However, the diagnostic accuracy of ultrasonography was higher in inactive liver cirrhosis and lower in active cirrhosis than that of serology (both P<0.05). False positive and false negative results where found when the diagnosis of compensated liver cirrhosis was made by ultrasonography. CONCLUSION: There are different ultrasonographic predictors for the evaluation of hepatic inflammation grade and fibrosis stage of chronic hepatitis. Both ultrasonography and serology have their own advantages and disadvantages in the evaluation of liver fibrosis and compensated liver cirrhosis. Combined application of the two methods is hopeful to improve the diagnostic accuracy.

Serum hyaluronic acid, procollagen type III and IV in histological diagnosis of liver fibrosis.

OBJECTIVE: To assess the significance of serum hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV) in the histological diagnosis of liver fibrosis. METHODS: The concentrations of serum HA, PCIII, CIV in 253 patients with chronic liver diseases were measured by radioimmunoassay. Liver biopsies were performed in all patients at the same time. The liver was pathologically evaluated by a pathologist according to a scoring system. Combined with the results of liver pathological diagnosis, the accuracy of serum HA, PCIII, CIV in diagnosing patients with hepatic fibrosis (staging >/=S2) or cirrhosis (S4) was assessed using the receiver operating curve (ROC). RESULTS: The cutoff values of serum HA, PCIII and CIV for identifying patients with hepatic fibrosis (>/=S2) or cirrhosis (S4) were determined. The cutoff values of serum HA, PCIII and CIV for detecting patients with fibrosis (stage >/=S2) were 90 micrograms/L, 90 micrograms/L, 75 micrograms/L, respectively; their sensitivity (Se) was 80.4%, 82%, 63.1%; their specificity (Spe) was 70.2%, 60.8%, 83.8%; their positive predictive values (PPV) were 86.7%, 83.5%, 90.4%; their negative predictive values (NPV) were 59.8%, 58.4%, 48.4%, respectively. The cutoff values for detecting patients with liver cirrhosis were 210 micrograms/L for HA, 96.2% for Se, 85.3% for Spe, 65.4% for PPV, 98.8% for NPV; 150 micrograms/L for PCIII, 76.4% for Se, 68.7% for Spe, 40.4% for PPV, 91.3% for NPV; 90 micrograms/L for CIV, 80% for Se, 75.8% for Spe, 47.8% for PPV, 93.2% for NPV, respectively. CONCLUSIONS: Serum HA, PCIII and CIV can be determined for an accurate diagnosis of hepatic fibrosis in various stages. HA is the best for screening liver cirrhosis.

The levels of serum fibrosis marks and morphometric quantitative measurement of hepatic fibrosis.

OBJECTIVE: To study the relationship between the serum levels of hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV) and the histological degree of hepatic fibrosis evaluated by image analysis, and the clinical significance of serum HA, PCIII, CIV in the diagnosis of hepatic fibrosis in patients with chronic viral hepatitis. METHODS: The concentrations of serum HA, PCIII, CIV in 151 patients with chronic viral hepatitis were measured by radioimmunoassay. Liver biopsies were performed in all the patients. Histological sections of 4 microm thickness were stained with Masson's trichrome for fibrosis assessment. Morphometric quantitative measurements for hepatic fibrosis assessment in the 4 microm sections were performed using a fully automated image analysis system. Serum levels of HA, PCIII, and CIV were analyzed at different stages of liver pathology and compared with the morphometric quantitative measurements of hepatic fibrosis. RESULTS: The serum levels of HA, PCIII, CIV all elevated gradually with the progression of the disease, and all reached the highest in patients with liver cirrhosis. There was a significant difference in the levels of these 3 components between liver cirrhosis group and the other groups (P<0.05). They all increased steadily with the histological stages of hepatic fibrosis, and reached the highest levels in stage IV. The serum levels of HA, PCIII, CIV were all positively correlated with the histological stages of liver sections and the morphometric measurement (P<0.001). The coefficients with stages were 0.694, 0.493, 0.552 (P<0.001), respectively and with surface density of total collagen on liver biopsy sections by image analysis were 0.715, 0.595, 0.573 (P<0.001), respectively. CONCLUSION: The serum levels of HA, PCIII, CIV were in consistent with the degree of hepatic fibrosis, and the determination of these marks is valuable for detecting hepatic fibrosis.