Liver Inflammation In Chronic Hepatitis Research Articles

SAT-510 - Establishment and validation of a diagnostic model for liver inflammation in chronic hepatitis B (CHB) patients concurrent with non-alcoholic fatty liver disease (NAFLD) based on machine learning (ML)

SAT-510 - Establishment and validation of a diagnostic model for liver inflammation in chronic hepatitis B (CHB) patients concurrent with non-alcoholic fatty liver disease (NAFLD) based on machine learning (ML)

Liver Stiffness Measurement can Predict Liver Inflammation in Chronic Hepatitis B Patients with Normal Alanine Transaminase.

To determine whether liver stiffness measurement (LSM) indicates liver inflammation in chronic hepatitis B (CHB) with different upper limits of normal (ULNs) for alanine aminotransferase (ALT). We grouped 439 CHB patients using different ULNs for ALT: cohort I, ≤40 U/L (439 subjects); cohort II, ≤35/25 U/L (males/females; 330 subjects); and cohort III, ≤30/19 U/L (males/females; 231 subjects). Furthermore, 84 and 96 CHB patients with normal ALT (≤40 U/L) formed the external and prospective validation groups, respectively. We evaluated the correlation between LSM and biopsy-confirmed liver inflammation, and determined diagnostic accuracy using area under the curve (AUC). A noninvasive LSM-based model was developed using multivariate logistic regression. Fibrosis-adjusted LSM values significantly increased with increasing inflammation. The AUCs of LSM in cohorts I, II, and III were 0.799, 0.796, and 0.814, respectively, for significant inflammation (A≥2) and 0.779, 0.767, and 0.770, respectively, for severe inflammation (A=3). Cutoff LSM values in all cohorts for A≥2 and A=3 were 6.3 and 7.5 kPa, respectively. Internal, external, and prospective validations showed high diagnostic accuracy of LSM for A≥2 and A=3, and no significant differences in AUCs among the four groups. LSM and globulin independently predicted A≥2. The AUC of an LSM-globulin model for A≥2 exceeded those of globulin, ALT, and AST, but was similar to that of LSM. LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.

Dose-response relationship between qAnti-HBc and liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase based on liver biopsy.

The proportion of chronic hepatitis B (CHB) patients with normal or mildly elevated alanine transaminase (NMALT) levels who have moderate to severe inflammation was not rare. However, we lacked appropriate biomarkers to evaluate liver inflammation in these populations. We aimed to explore the relationship between quantitative hepatitis B core antibody (qAnti-HBc) and hepatic histological inflammation. This multicenter cohort study enrolled participants from 34 Chinese hospitals including 1376 treatment-naive CHB patients with liver biopsy (934 with NMALT entered treatment-naive cohort; 423 with secondary liver biopsy entered treatment cohort). Using unadjusted and multivariate-adjusted generalized linear models, generalized additive models with smooth curve fitting, we evaluated the associations between qAnti-HBc and liver inflammation in these patients. In the treatment-naive patients, qAnti-HBc was positively associated with liver inflammation (histology activity index [HAI] evaluated by Ishak scoring system; fully adjusted model: β = 0.48, 95% confidence interval [CI] [0.30-0.66], p < 0.001). For per-SD increase in qAnti-HBc, the risk of moderate to severe inflammation (HAI ≥ 5) increased by 56% (odds ratio [OR] = 1.56, 95% CI [1.28-1.91], p < 0.001). The curve fitting indicated a significant "threshold effect" (inflection point was 4.5 log10 IU/ml, p < 0.001). Subgroup analyses and interactions were not significant (all p > 0.05). In the treatment patients, there was no significant correlation between qAnti-HBc and liver inflammation, whether based on unadjusted, minimally adjusted, or fully adjusted models (all p > 0.100). Paired analyses showed a significant correlation between decreasing in qAnti-HBc and alleviation of liver inflammation. qAnti-HBc was positively correlated with liver inflammation in treatment-naive CHB patients with NMALT. The cutoff value of qAnti-HBc for the diagnosis of moderate to severe inflammation was 4.5 log10 IU/ml. Decreasing in qAnti-HBc was positively correlated with liver inflammation relieving.

Association of anti-HBc and liver inflammation in HBeAg-negative chronic hepatitis B virus-infected patients with normal ALT and detectable HBV DNA.

Serum hepatitis B core antibody (anti-HBc) is associated with liver inflammation in chronic hepatitis B patients. This study aimed to investigate whether anti-HBc could serve as a predictor of significant liver inflammation in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infected patients with normal alanine aminotransferase (ALT) and detectable HBV DNA. Treatment-naïve HBeAg-negative chronic HBV infected patients with normal ALT and detectable HBV DNA who underwent liver biopsy were retrospectively included from two medical centers. Liver inflammation grade was evaluated using the Scheuer scoring system and significant liver inflammation was defined as ≥G2. Serum anti-HBc levels were measured by commercial immunoassays (Abbott GmbH & Co. KG). A total of 117 patients were included and 50 (42.7%) patients showed significant liver inflammation. Serum anti-HBc levels in patients with significant liver inflammation were significantly higher than patients with no or mild liver inflammation (<G2) (p < 0.001). High serum anti-HBc (odds ratio 1.562, 95% confidential interval 1.157-2.110, p = 0.004) was an independent risk factor of significant liver inflammation. The area under the receiver operating characteristic curve of serum anti-HBc in predicting significant liver inflammation was 0.769 and the optimal cut-off value was 10.87 S/CO, with a sensitivity of 59.2% and a specificity of 87.9%. Our data revealed that a substantial of HBeAg-negative chronic infection patients with normal ALT and detectable HBV DNA showed significant liver inflammation. Serum anti-HBc can predict significant liver inflammation in these patients.

Role of tumor necrosis factor-α, interleukin-1β, interleukin-6 in liver inflammation in chronic hepatitis B and chronic hepatitis C

Role of tumor necrosis factor-α, interleukin-1β, interleukin-6 in liver inflammation in chronic hepatitis B and chronic hepatitis C

Clinical Non-invasive Model to Predict Liver Inflammation in Chronic Hepatitis B With Alanine Aminotransferase ≤ 2 Upper Limit of Normal.

Background and Aim: Liver biopsy remains the gold standard for evaluating liver histology. However, it has certain limitations, and many patients refuse it. Non-invasive methods of liver evaluation are thus attracting considerable interest. In this study, we sought predictors of liver inflammation in chronic hepatitis B (CHB) patients with alanine aminotransferase (ALT) levels ≤ 2-fold the upper limit of normal (ULN); these may guide decisions on whether to commence antiviral therapy.Methods: We retrospectively analyzed 720 patients with CHB who underwent liver biopsy and whose ALT levels were ≤2 ULN. The patients were randomly divided into a training and validation set. We used univariate and multivariate regression analyses of data from the training set to construct a model that predicted significant (grade ≥2) liver inflammation, and validated the model employing the validation set.Results: Aspartate aminotransferase (AST) level, prothrombin time (PT), glutamyl transpeptidase (GGT) level, and anti-hepatitis B virus core antibody (anti-HBC) level were independent predictors of significant liver inflammation in CHB patients with ALT levels ≤ 2 ULN. A model featuring these four parameters afforded areas under the ROC curve of 0.767 and 0.714 for the training and validation sets. The model was more predictive than were the individual factors.Conclusion: AST, GGT, anti-HBC, and PT reflect significant liver inflammation among CHB patients with ALT levels ≤ 2 ULN. Their combination indicates whether antiviral therapy is required.

Persistent liver inflammation in chronic hepatitis C patients with advanced fibrosis after direct-acting antivirals induced sustained virological response.

Direct-acting antivirals (DAA) improve sustained virological response (SVR) rates with normalization of liver enzymes in patients with hepatitis C. However, liver inflammation may persist despite virus eradication. We aimed to investigate the rate and risk factors for persistent elevated aminotransferase levels in patients with advanced fibrosis after DAA-induced SVR. From January 2017 to April 2018, chronic hepatitis C patients with advanced fibrosis and SVR after DAA treatment at the Taipei Veterans General Hospital were prospectively enrolled. Persistent liver inflammation after SVR was defined as an increase in levels of alanine aminotransferase (ALT) (>40 U/L) at SVR12. A total of 461 patients were included (57.9% females, mean age 64 years, 69.6% genotype 1b, 46.4% cirrhosis). At SVR12, there was a decline in ALT levels (90.5 ± 80.8 U/L to 25.3 ± 26.5 U/L) from baseline levels. Persistent liver inflammation at SVR12 was detected in 45 patients (9.8%). The presence of cirrhosis, markers of impaired liver functions, history of interferon-based therapy, steatosis, and elevated ALT levels at baseline was associated with persistent liver inflammation after SVR12. Results of multivariate analysis indicated that levels of baseline serum total bilirubin (odds ratio [OR]: 2.605, 95% CI: 1.158-5.858), international normalized ratio (OR: 14.389, 95% CI: 1.754-118.049), ALT (OR: 1.006, 95% CI: 1.003-1.009), and the presence of steatosis (OR: 3.635, 95% CI: 1.716-7.698) were independent predictors of persistent liver inflammation at SVR12. Persistent liver inflammation is not uncommon in chronic hepatitis C patients with advanced fibrosis after DAA-induced SVR. It is associated with impaired baseline liver function and steatosis. Long-term follow-up is required to assess the implication of liver inflammation on disease progression.

Serum sCD14 as a Biomarker for Significant Liver Inflammation in Chronic Hepatitis B Patients with Normal or Mildly Elevated ALT.

CD14 is a pattern recognition receptor constitutively expressed in different types of immune cells, either in a membrane-anchored (mCD14) or in a soluble (sCD14) form. This study investigated whether hepatic CD14 expression levels were correlated with the grades of liver inflammation as well as the potential usefulness of serum sCD14 as a biomarker for predicting liver inflammation in chronic hepatitis B (CHB) patients with normal or mildly elevated ALT. A total of 216 treatment-naive CHB patients with normal or mildly elevated ALT who underwent liver biopsy were recruited. Hepatic expression level of CD14 was measured using immunohistochemistry and real-time PCR. Serum sCD14 concentrations were determined with an enzyme-linked immunosorbent assay. Correlations between hepatic CD14, serum sCD14, and liver inflammation grade were analyzed. Univariate and multivariate analysis were performed to identify significant liver inflammation-associated factors. The receiver operating characteristic curve was used to assess the discriminating power of serum sCD14 to significant liver inflammation in CHB patients with normal or mildly elevated ALT. Both hepatic expression levels of CD14 and serum sCD14 concentrations significantly increased with the aggravation of liver inflammation. Moreover, hepatic expression levels of CD14, serum sCD14 concentrations, and liver inflammation grades were positively correlated with each other. Three parameters including alkaline phosphatase (ALP), neutrophil, and sCD14 were identified as independent predictors of significant liver inflammation. Subsequently, a diagnostic equation named model-sCD14 was developed incorporating sCD14 and other variables (ALP and neutrophils) with p < 0.05 in multivariate logistic analysis. The area under receiver operating characteristic curve (AUC) of sCD14 for predicting significant liver inflammation was 0.788 and the optimal cutoff was 27.14 ng/mL, with a sensitivity of 66.67%, a specificity of 81.70%, positive predictive value of 60.01%, and negative predictive value of 85.62%. When sCD14 was replaced by model-sCD14, the AUC value increased from 0.788 to 0.843 (z = 2.311, p = 0.021), with sensitivity of 77.78%, specificity of 77.12%, positive predictive value of 58.33%, and negative predictive value of 89.39%. Serum sCD4 has the potential to discriminate significant liver inflammation from CHB patients with normal or mildly increased ALT levels.

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

SummaryBackgroundGuidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.AimTo study rates and determinants of clinically significant liver inflammation.MethodsWe selected patients with HBV DNA > 2000 IU/mL from the SONIC‐B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).ResultsThe cohort included 2991 patients; 1672 were HBeAg‐positive. ALT was < ULN in 270 (9%), 1‐2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1‐2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.ConclusionsAmong patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non‐invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.

Study of reactive oxygen species and adiponectin for chronic HBV infection combined with nonalcoholic fatty liver diseases

Objective: To investigate the application value of reactive oxygen species (ROS) and adiponectin (ADPN) in the judgment of liver inflammation in chronic hepatitis B virus infection combined with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 159 cases with NAFLD (21 cases), chronic hepatitis B virus infection (57 cases), and chronic hepatitis B virus infection combined with NAFLD (81 cases) were collected between June 2016 to December 2018, and the visited patients diagnosis were confirmed by histopathological examination of the liver. ROS and ADPN level retained in serum was determined by enzyme-linked immunosorbent assay. Histopathological examination of liver tissue was used as the gold standard to discuss the diagnostic value of the serum in patients with chronic hepatitis B virus infection combined with NAFLD for the occurrence of nonalcoholic steatohepatitis. One-way analysis of variance was used for the comparison among multiple groups, and LSD-t test was used for pairwise comparison between groups. Measurement data for non-normal distributions were expressed as M (P25, P75). Comparisons between groups were performed using the Mann-Whitney U or Kruskal-Wallis H test. Chi-square test was used to compare the count data between groups. Correlation analysis was performed using Spearman correlation analysis. Histopathological grouping of liver tissue was used as the gold standard, and the area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the regression formula. Results: (1) In patients with chronic hepatitis B virus infection combined with NAFLD, the levels of ROS in the non-hepatic steatosis group and the mild hepatic steatosis group were significantly lower than those in the moderate and severe hepatic steatosis group, while the ADPN level in the non-hepatic steatosis group was significantly higher than liver steatosis group, P < 0.05. (2) The results of correlation analysis showed that ROS was significantly correlated with NAS score, change in the degree of fatty liver and lobular inflammation (all P < 0.05).There was a significant negative correlation between ADPN and the change in the degree of fatty liver (P < 0.05). (3) Logistic regression analysis results showed that the diagnostic formula for chronic hepatitis B virus infection combined with nonalcoholic steatohepatitis was 0.02 × controlled attenuation index + 0.584 × white blood cells/10(9) + 0.587 × ROS-10.982. The area under receiver operating characteristic curve of the subject was = 0.896. The sensitivity, specificity, positive and negative predictive value were 97.1%, 71.2%, 64.2%, and 97.9%. Conclusion: ADPN and ROS have certain reference value in differentiating the change in the degree of fatty liver and inflammation in chronic hepatitis B virus infection combined with NAFLD and the diagnostic formula has higher application value in the diagnosis and exclusion of chronic hepatitis B virus infection combined with nonalcoholic steatohepatitis.

The gamma-glutamyl transpeptidase to platelet ratio predicts liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase

The gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) was proposed as a novel index for predicting liver inflammation in chronic hepatitis B (CHB) patients. We aimed to investigate GPR for predicting significant liver inflammation in CHB patients with normal (≤1×upper limit of normal, ULN) or mildly elevated (≤2×ULN) alanine transaminase (ALT). 431 treatment-naïve CHB patients with normal or mildly elevated ALT who underwent liver biopsy were enrolled. Comparision of GPR and other parameters for significant liver inflammation (G≥3). For patients with ALT≤2×ULN, the receiver-operating characteristic curves (AUROCs) of GPR in predicting significant liver inflammation were 0.837 (95%CI 0.796 to 0.878), 0.860 (95%CI 0.809 to 0.910) and 0.809 (95%CI 0.739 to 0.878) in the entire patients, HBeAg positive and HBeAg negative CHB patients, respectively. The diagnostic performance of GPR was higher than ALT (P<0.001, P<0.001, respectively), aspartate transaminase (AST) (P=0.001, P=0.003, respectively) and GGT (P=0.002, P=0.002, respectively) in the entire and HBeAg positive patients, but was comparable with AST (P=0.096) and GGT (P=0.273) in the HBeAg negative CHB patients. For patients with ALT≤1×ULN, the diagnostic accuracy of GPR was significantly higher than ALT, AST and GGT in the entire (P<0.001, P=0.008 and P=0.043, respectively) and HBeAg positive CHB patients (P<0.001, P=0.009 and P=0.024, respectively), while was comparable to AST (P=0.209) and GGT(P=0.555) in the HBeAg negative CHB patients. GPR has a better diagnostic value than conventional parameters to predict significant liver inflammation in CHB patients with normal or mildly elevated ALT levels, especially for HBeAg positive CHB.

Serum GP73 combined AST and GGT reflects moderate to severe liver inflammation in chronic hepatitis B

BackgroundNon-invasive method to identify chronic hepatitis B (CHB) patients with at least moderate inflammatory lesion but no increased ALT is an unmet need.We evaluated Golgi protein 73 (GP73) based hepatic inflammation model (HIM) as a serum surrogate for liver necroinflammatory activity, especially in those with ALT less than traditional upper concentration. MethodsThe diagnostic performances of HIM were evaluated in 2 independent cohorts of liver biopsy proved CHB patients by receiver operating characteristic (ROC) curve analysis. ResultsHIM, a suggested index combined GP73, gamma-glutamyltransferase and AST, could significantly improve the diagnostic accuracy for liver necroinflammation (Area under ROC, AUROC: 0.890). More importantly, HIM still exhibit excellent diagnostic value (AUROC: 0.873) to identify patients with at least moderate liver necroinflammatory activity but with ALT <40 U/l. Serum GP73 was the major source of improvement for diagnostic model's accuracy. ConclusionHIM is probably a promising non-invasive index to identify CHB patients with moderate to severe liver necroinflammation, especially in those with ALT <40 U/l.

A novel diagnostic algorithm to predict significant liver inflammation in chronic hepatitis B virus infection patients with detectable HBV DNA and persistently normal alanine transaminase

Significant liver inflammation might be found in 20–34% of chronic hepatitis B virus (HBV) infection patients with detectable HBV DNA and persistently normal alanine transaminase (ALT) (PNALT). We aimed to develop a diagnostic algorithm to predict significant liver inflammation in these specific patients. Using liver biopsy as the gold standard, we developed a novel, simple diagnostic algorithm to predict significant liver inflammation in a training set of 365 chronic HBV infection patients with detectable HBV DNA and PNALT, and validated the diagnostic accuracy in a validation set of 164 similar patients. The novel algorithm (AAGP) attributed to age, ALT, gamma-glutamyl transpeptidase (GGT), and platelet count was developed. In the training set, the area under the receiver operating characteristic curve (AUROC) of AAGP was higher than that of ALT and aspartate transaminase (AST), to diagnose significant liver inflammation (0.77, 0.67, and 0.59, respectively, p < 0.001). In the validation set, the AUROC of AAGP was also higher than ALT and AST (0.75, 0.61, and 0.54, respectively, p < 0.001). Using AAGP ≥2, the sensitivity and negative predictive value (NPV) was 91% and 93%, respectively, to diagnose significant liver inflammation. Using AAGP ≥8, the specificity and NPV was 91% and 86%, respectively, for significant liver inflammation. In conclusion, the AAGP algorithm is a novel, simple, user-friendly algorithm for the diagnosis of significant liver inflammation in chronic HBV infection patients with detectable HBV DNA and PNALT.

SAT-086 - The gamma-glutamyl transpeptidase to platelet ratio: a novel index for predicting significant liver inflammation in chronic hepatitis B

SAT-086 - The gamma-glutamyl transpeptidase to platelet ratio: a novel index for predicting significant liver inflammation in chronic hepatitis B

Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near‐normal alanine aminotransferase levels

Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross-sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732-0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients.

Serum hepatitis B core antibody as a biomarker of hepatic inflammation in chronic hepatitis B patients with normal alanine aminotransferase

Our previous studies unexpectedly indicated that the level of serum hepatitis B core antibody (anti-HBc) was positively correlated with the serum alanine aminotransferase (ALT) level. The aim of this study was to determine whether anti-HBc could serve as a potential biomarker for the detection of liver inflammation in chronic hepatitis B (CHB) patients, especially in patients with normal ALT levels. Serum anti-HBc levels were quantified in 655 treatment-naïve CHB patients, including 45 patients who underwent two liver biopsies (baseline phase and the 78th weeks of antiviral-treatment). Serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score. After antiviral-treatment, patients with HAI score reduction had significant decline in serum anti-HBc level. Multivariate analysis showed that anti-HBc was independently associated with moderate-to-severe hepatic inflammation in patients with normal ALT level. Furthermore, serum anti-HBc showed a high diagnostic accuracy for predicting moderate-to-severe inflammation in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients with normal ALT levels (area under the curve, AUC = 0.87 and 0.75; respectively). Thus, anti-HBc may be a strong indicator for assessing the hepatic inflammatory degree and used for antiviral treatment decisions in CHB patients with normal ALT levels.

Quantitative intrahepatic HBV cccDNA correlates with histological liver inflammation in chronic hepatitis B virus infection

The aim of this study was to determine the role of baseline hepatitis B virus (HBV) forming covalently closed circular DNA (HBV cccDNA) in liver inflammation in patients infected with HBV with serum alanine aminotransferase (ALT) levels under two times the upper limit of normal (2×ULN). After liver biopsy and serum virological and biochemical marker screening, patients diagnosed with chronic HBV infection with serum ALT levels under 2×ULN and histological liver inflammation of less than grade G2 were prospectively recruited into this study. Recruitment took place between March 2009 and November 2010 at the Center of Infectious Disease, Sichuan University. Patient virological and biochemical markers, as well as markers of liver inflammation, were monitored. A total of 102 patients were recruited and 68 met the inclusion criteria; the median follow-up was 4.1 years (range 3.9-5.2 years). During follow-up, 41 patients (60.3%) exhibited signs of inflammation. Baseline HBV cccDNA >1 copy/cell (odds ratio 9.43, p=0.049) and liver inflammation grade ≥G1 (odds ratio 5.77, p=0.046) were both independent predictors of liver inflammation. A higher baseline intrahepatic HBV cccDNA level may increase the risk of liver inflammation. Further investigations will be required to validate HBV cccDNA as an intrahepatic virological marker of patients who require extended outpatient management.

Expression profiles of circulating cytokines, chemokines and immune cells in patients with hepatitis B virus infection.

Background:Immune cells and molecules play a vital role in initiating, maintaining, regulating immunological homeostasis and inflammation in many pathological and physiological processes; however, the changes on expressions and functions of these cells and molecules in hepatitis B virus (HBV) infection have not been elucidated well.Objectives:The current study aimed to determine the expression pattern of different cytokines, chemokines, immune cells in HBV infection and their association with disease progression.Patients and Methods:Sixty-nine patients with chronic HBV infection were enrolled. Five immune cell subsets and 46 cytokines and chemokines were analyzed by flow cytometry and Luminex 200.Results:In comparison to healthy individuals and asymptomatic HBV carriers, expression of CXCL9, CXCL10, CXCL11, and IL-10 were elevated in patients with chronic active HBV and had positive correlation with ALT levels. In contrast, G-CSF, MCP-3, and IFN-γ levels were significantly decreased in patients with chronic active HBV infection in contrast to carriers and healthy individuals; however, these down regulations did not show any correlation with either virological findings or liver inflammation. Although the proportion of CD4+ CD25 high regulatory T cells (Tregs) was higher in patients with HBV infection than in healthy controls, no correlations were found between Tregs and other cytokines or chemokines.Conclusions:CXCR3-associated chemokines might contribute to liver inflammation in chronic hepatitis B, while MCP-3 and G-CSF were inhibited by HBV infection. Host immune response was suppressed as manifested by an increase in CD4+ CD25high Tregs and IL-10 as well as a decrease in IFN-γ. Exploiting the expression pattern of cytokine and chemokine may help to develop a better understanding of chronic HBV infection pathogenesis.

Presence of valine at position 27 of the hepatitis B virus core gene is associated with severe liver inflammation in Chinese patients

Although it is widely believed that cytotoxic T lymphocytes (CTL) are responsible for severe flares of chronic hepatitis B that lead to liver failure, the published evidence to support this hypothesis is weak. The frequency of the I27V mutation in the HBV core gene, which produces a core 18-27 peptide capable of binding HLA-A*02, was compared in Chinese patients with severe liver inflammation (n = 77, including 39 with acute-on-chronic liver failure), moderate liver inflammation (n = 44) and inactive disease (n = 45). The frequency with which V27 reverted to the wild-type I27 was compared in severe liver inflammation patients who were either HLA-A*02 positive (n = 5) or negative (n = 5). The frequency of patients with a V27 positive HBV was higher in severe than in moderate liver inflammation (23.4% vs. 6.8%, P = 0.02) or inactive disease (23.4% vs. 4.7%, P = 0.006). After a minimum of 3 months follow-up, the frequency of reversion of V27 to the wild-type I27 was higher in HLA-A*02 positive than negative patients (5/5 vs. 1/5, P = 0.05). In summary, this is the first data showing an association between a specific amino acid mutation (I27V) and severe liver inflammation in patients with chronic hepatitis B. This mutation would produce a peptide that is known to bind HLA-A*02 and stimulate CTL. The high frequency of reversion to wild-type I27 in HLA-A*02 positive subjects suggests that CTL recognizing this peptide exist, and is consistent with the possibility that they contribute to the pathophysiology of severe liver inflammation in chronic hepatitis B.

Intrahepatic levels of PD-1/PD-L correlate with liver inflammation in chronic hepatitis B

Programmed cell death-1 (PD-1) represents a mechanism of T-cell dysfunction in hepatitis B virus (HBV) persistence. In peripheral blood, PD-1 is up-regulated in virus-specific T cells, leading to the impairment of T cells. This study investigated the intrahepatic expression of PD-1 and its ligand (PD-L) in patients with chronic hepatitis B (CHB) virus. Liver specimens were obtained from CHB (n = 56), acute hepatitis B (AHB, n = 12) patients and age-matched healthy subjects (n = 10). The expression of PD-1/PD-L was determined by immunohistochemistry. In CHB patients, PD-1 was predominantly expressed in lymphocytes infiltrating the portal tract. PD-L1 was detected in lymphocytes, hepatocytes and liver sinusoidal endothelial cells, while PD-L2 was localized in Kupffer cells and dendritic cells. The labeling indexes of PD-1 and PD-L1 in lymphocytes infiltrating portal area were significantly higher in CHB patients than in healthy controls and AHB patients. Within the CHB patients, the increases in labeling indexes of PD-1 and PD-L paralleled the degree of inflammation. These results suggest that over-expression of PD-1, PD-L1 and PD-L2 within liver may participate in local immune dysfunction, which could be one of the mechanisms involved in the chronicity of HBV infection and chronic inflammation seen in CHB patients.