Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

HBeAg-negative chronic hepatitis patients should be monitored more strictly: a cross-sectional retrospective study on antiviral treatment-naïve patients.

AIM: To investigate the prevalence and characteristics of hepatitis B e antigen (HBeAg) negative/treatment naïve subjects with low hepatitis B virus (HBV) DNA levels (<10(4) copies/ml) and low alanine aminotransferase (ALT) levels (<2 × upper limit of normal) in patients with HBV-related hepatocellular carcinoma (HCC). METHODS: A total of 226 treatment naïve patients diagnosed with HBV-related HCC, divided into five Barcelona Clinic Liver Cancer (BCLC) stages, were enrolled and retrospectively analyzed. Virological parameters including hepatitis B surface antigen (HBsAg), HBeAg, HBV DNA levels, and laboratory parameters including ALT and aspartame aminotransferase were accessed at the time of HCC was diagnosed. Comparison between HBeAg positive patients and HBeAg negative patients was performed using a χ(2) test. RESULTS: While laboratory parameters correlated with BCLC stages, virological parameters did not. HBeAg negative patients were more prevalent than HBeAg positive patients (160, 70.8% vs. 66, 29.2%). HBsAg and HBV DNA levels in HBeAg negative patients were significantly lower than that in HBeAg positive patients (all P < 0.001). Of the 160 HBeAg negative patients, 74 (46.25%) had low HBsAg, 76 (47.5%) had low DNA levels, and 35 (21.9%) patients had low DNA and normal ALT levels. CONCLUSIONS: In treatment naïve patients with HBV-related HCC, the majority (70.8%) were HBeAg negative patients. More than one fifth of HBeAg negative patients had low HBV DNA levels and normal ALT levels, indicating more strict monitoring for HBeAg negative patients is needed.

Hepatitis B surface antigen in late hepatitis B infection.

Hepatitis B surface antigen (HBsAg) levels are used to evaluate and monitor clinical phases of chronic hepatitis B infection but their clinical significance is unclear in the late complications, cirrhosis of the liver and hepatocellular carcinoma. This study aimed to evaluate HBsAg levels across the whole natural history of hepatitis B virus infection, including late complications. This retrospective, cross-sectional study enrolled 838 treatment-naive patients diagnosed with chronic hepatitis B infection at First Affiliated Hospital of Fujian Medical University between 2009 and 2012. Patients were classified into six groups: immunotolerance, immunoclearance, low replicative, negative hepatitis e (HBeAg) phases, liver cirrhosis, and hepatocellular carcinoma. Main outcome measures were serum HBsAg, HBeAg, HBV DNA, total bilirubin, albumin, alanine and aspartate aminotransferase, and quantitative correlation of HBsAg with HBV DNA. HBsAg levels declined significantly between clinical phases of infection (all P < 0.001) and were significantly lower in decompensated than in compensated cirrhosis (2.90 vs. 3.30, P < 0.001) but not significantly different between early versus advanced hepatocellular carcinoma. Significant positive correlations were observed between serum HBsAg and HBV DNA at immunoclearance and HBeAg negative phases, compensated and decompensated liver cirrhosis and advanced but not early hepatocellular carcinoma (all P < 0.001). HBsAg and HBV DNA were significantly higher in HBeAg positive patients with advanced hepatocellular carcinoma (P < 0.001). HBsAg levels differ significantly between chronic hepatitis B infection phases, decreasing progressively from chronic infection to cirrhosis and hepatocellular carcinoma. Significant correlations are found between serum HBsAg and HBV DNA.

Alpha-fetoprotein level as a biomarker of liver fibrosis status: a cross-sectional study of 619 consecutive patients with chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV) infection is a serious public health problem worldwide. This study aimed to investigate the relationship between serum alpha-fetoprotein (AFP) levels and pathological stages of liver biopsy in patients with chronic hepatitis B (CHB). METHODS: The study included 619 patients who were diagnosed with CHB from March 2005 to December 2011. AFP levels were measured by electrochemiluminescence. Liver biopsy samples were classified into five levels of inflammation (G) and fibrosis (S) stages, according to the Chinese guidelines for prevention and treatment of viral hepatitis. Two multivariable ordinal regression models were performed to determine associations between AFP, GGT, and APRI (AST/PLT ratio) and stages of inflammation and fibrosis. RESULTS: Significant positive and moderate correlations were shown between AFP levels and inflammation stages and between AFP levels and fibrosis stages (ρ = 0.436 and 0.404, p < 0.001). Median values of AFP at liver fibrosis stages S0-1, S2, S3, and S4 were 3.0, 3.4, 5.4, and 11.3 ng/ml, respectively, and median APRI (AST/PLT ratio) was 0.41. Receiver operating characteristic (ROC) curve analyses revealed that the areas under the curves (AUCs) were 0.685, 0.727, and 0.755 (all p <0.001) for judging inflammation stages of G ≥ 2, G ≥ 3, G = 4 by AFP; and 0.691, 0.717, and 0.718 (all p <0.001) for judging fibrosis stages of S ≥ 2, S ≥ 3, and S = 4 by AFP. APRI levels showed significant positive and moderate correlations with inflammation stages (ρ = 0.445, p < 0.001). AST, GGT, and APRI levels showed significant positive but very weak to weak correlations with fibrosis stages (ρ = 0.137, 0.237, 0.281, p < 0.001). CONCLUSIONS: Serum AFP levels increased as pathological levels of inflammation and fibrosis increased in CHB patients. Our data showed the clinical significance of serum AFP levels in diagnosing liver inflammation and fibrosis. Assessment of liver pathology may be improved by creating a predictive mathematical model by which AFP levels with other biomarkers.

Diagnostic value of liver stiffness measurement combined with risk scores for esophagogastric variceal bleeding in patients with hepatitis B cirrhosis.

PURPOSE: To assess the predictive value of liver stiffness measurement (LSM) and three bleeding risk scoring systems for esophagogastric varices bleeding (EGVB) in patients with hepatitis B cirrhosis during hospitalization. METHODS: In this study, 210 patients who had hepatitis B cirrhosis were selected as the subjects. They were categorized into two groups based on whether EGVB occurred during hospitalization: a bleeding group (70 cases) and a non-bleeding group (140 cases). Logistic regression was used to analyze the factors related to the occurrence of EGVB, and the diagnostic performance was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: Significant differences were observed between the two groups in systolic blood pressure, platelet count, albumin, urea nitrogen, LSM, pre-endoscopic Rockall score (PRS), Glasgow-Blatchford score (GBS), and AIMS65 score (P < 0.05). The correlation analysis showed that LSM had significant positive relationship with PRS, GBS and AIMS65 score. Logistic regression analysis revealed that LSM and GBS score were independent risk factors for EGVB occurrence during hospitalization. ROC curve analysis showed that the combined prediction model of LSM and GBS score had the best prediction performance for EGVB occurrence, with an ROC curve area of 0.811, which was significantly better than the three risk scoring systems (P < 0.05), but similar to the predicted value of LSM (P = 0.335). CONCLUSIONS: The combination of LSM and GBS score can significantly improve the predictive efficacy of EGVB occurrence in patients with hepatitis B cirrhosis during hospitalization, which has important clinical significance for patients' prognosis.

Determining optimal ALT cut-off values for predicting significant hepatic histological changes in patients with normal ALT in the grey zone of chronic hepatitis B virus infection.

BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.

Hepatitis B Virus Envelope Antigen and Hepatitis B Virus Surface Antigen Both Contribute to the Innate Immune Response During Persistent Hepatitis B Virus Infection.

This study aimed to investigate the changes of toll-like receptor 4 (TLR4), proinflammatory cytokine expression, hepatitis B virus surface antigen (HBsAg), and hepatitis B virus envelope antigen (HBeAg) expression as well as innate immune cell percentages in a mouse model of persistent hepatitis B virus (HBV) infection to better understand the innate immune response. Mouse models of persistent HBV infection, HBsAg expression, and HBeAg expression were developed using high-pressure tail-vein injection of recombinant adeno-associated viruses. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum proinflammatory cytokine levels. Immunohistochemistry and western blot assays were used to detect TLR4 expression. Flow cytometric analysis was used to assess the percentage of innate immune cells in the whole blood. Persistent HBV infection, HBsAg expression, and HBeAg expression each significantly decreased the expression of TLR4. Persistent HBV infection significantly increased the percentages of T cells and monocytes, whereas it decreased the percentage of natural killer (NK) cells. Persistent HBeAg expression also decreased the percentage of NK cells, whereas persistent HBsAg expression increased the percentage of NK cells. Both persistent HBsAg and HBeAg expression increased the percentage of monocytes. However, both persistent HBsAg and HBeAg expression decreased the percentage of T cells. HBV as well as HBsAg and HBeAg showed similar effects on the expression of TLR4 and proinflammatory cytokines as well as the percentage of monocytes. Persistent HBV infection increased the percentage of T cells and decreased the percentage of NK cells, whereas only persistent HBeAg expression contributed to a decreased percentage of NK cells.

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

Background and Aims: 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). Methods: 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. Results: 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. Conclusions: LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.

[Relationship between the changes in immune cells and HBeAg loss following antiviral treatment in chronic hepatitis B patients].

OBJECTIVE: To observe the changes in hepatitis B virus (HBV)-specific and non-specific cellular immunity that accompany viral load decline during adefovir dipivoxil (ADV) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, and to explore the antiviral immunity mechanism underlying the treatment response. METHODS: Serial analysis of cellular immunological parameters was performed in HBeAg-positive patients (n = 20) throughout the 48-week course of ADV therapy (10 mg/d). HBV-specific T cell reactivity to HBV core antigen (HBcAg) was assessed by enzyme-linked immunosorbent spot assay and cell proliferation assay at pre-treatment (baseline) and post-treatment weeks 4, 12, 24, 36, and 48. Percentage of regulatory T cells (Tregs), as well as activated peripheral natural killer (NK) cells (expressing the NKG2D receptor), was measured by flow cytometry. Comparisons of means were performed by the two-tailed t-test or the Mann-Whitney rank sum test. RESULTS: After 48 weeks of ADV therapy, HBeAg loss was observed in six of the 20 (30%) patients and 14 patients remained HBeAg-positive. In the patients with HBeAg loss, the viral load reduction was accompanied by a significantly enhanced response rate of HBV-specific interferon (IFN)-gamma-producing CD4+ T cells [measured as (spot forming cells/peripheral blood mononuclear cells); baseline: (661.25+/-281.97) *10(-6) vs. week 48: (280.75+/-104.33) *10(-6), P = 0.045]. In contrast, patients without HBeAg loss showed no significant differences in T cell response rates. The patient groups with and without HBeAg loss showed similar proportions of peripheral blood Tregs during the treatment course, which included a trend of gradual decrease from baseline to week 4 with steady levels thereafter. In addition, both groups showed a similar increase in NKG2D expression that began at week 12 and peaked at week 48. CONCLUSION: HBV-specific T cell reactivity temporally increases in some ADV-treated chronic hepatitis B patients, and this trend is strongly associated with HBeAg loss. Furthermore, recovery of HBV-specific T cell reactivity promotes viral clearance and HBeAg seroconversion.

[Relation between HBsAg levels during the immune clearance phase of hepatitis B virus infection and liver pathological stages of chronic hepatitis B].

OBJECTIVE: To investigate whether the level of hepatitis B surface antigen (HBsAg) represents the status of inflammation and stages of fibrosis in livers of patients with chronic hepatitis B (CHB) during the immune clearance phase (IC). METHODS: Liver biopsy samples and sera were collected from 165 consecutive patients (136 males; 29 females) with CHB in IC who were treated in our hospital between March 2009 and June 2011. Routine biochemical tests were carried out to measure indicators of liver function. The relation between HBsAg level and liver pathological stages were determined by Spearman's rank correlation analysis. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of HBsAg level for liver pathological stages. Binary logistic regression was used to analyze potentially relevant indicators, and liver pathology-predicting models were built and analyzed by the ROC method. RESULTS: The mean values of HBsAg (IU/mL) were significantly different at the different liver inflammation stages: G1, 27 716.07+/-32 870.69; G2, 34 478.75+/-40 899.55; G3, 19 408.09+/-24 881.07; G4, 14 286.31+/-28 610.14. Likewise, the mean values of HBsAg (IU/mL) were significantly different at the different liver fibrosis stages: S1, 41 337.23+/-43 236.39; S2, 27 264.32+/-32 517.29; S3, 111 541.77+/-11 538.93; S4, 11 447.37+/-22215.44. Spearman's rank correlation analysis indicated a significant correlation between HBsAg level and liver inflammation stage (rs = -0.244) and fibrosis stage (rs = -0.365). ROC curve analysis of the diagnostic value of HBsAg for inflammation stages S more than or equal to 4 revealed that the area under the curve (AUC) was 0.70. The specificity of diagnosing S more than or equal to 4 was > 95.16% when HBsAg was less than or equal to 32995 IU/mL. Binary logistic regression analysis identified age, serum albumin, cholinesterase, and HBsAg as independent predictors of liver fibrosis. CONCLUSION: HBsAg level is negatively correlated with liver inflammation and fibrosis stages for patients with CHB in the IC phase, and might represent a useful noninvasive marker of the degree of hepatic fibrosis.

Gut microbiota of hepatitis B virus-infected patients in the immune-tolerant and immune-active phases and their implications in metabolite changes.

BACKGROUND: The microbes and metabolomics of microbiota dysbiosis in the gut in the different phases of hepatitis B virus (HBV) infection are not fully understood. AIM: To investigate the specific gut microbiota and metabolites of the immune-tolerant (IT) and immune-active (IA) phases of chronic hepatitis B (CHB). METHODS: Clinical fecal samples from healthy individuals and patients in the IT and IA phases of HBV infection were collected. Next, non-target metabolomics, bioinformatics, and 16S rDNA sequencing analyses were performed. RESULTS: A total of 293 different metabolites in 14 phyla, 22 classes, 29 orders, 51 families, and 190 genera were identified. The four phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the most abundant, accounting for 99.72%, 99.79%, and 99.55% in the healthy controls, IT-phase patients, and IA-phase patients, respectively. We further identified 16 genera with different richness in the IT phase and IA phase of HBV infection. Of the 134 named metabolites, 57 were upregulated and 77 were downregulated. A total of 101 different metabolic functions were predicted in this study, with 6 metabolic pathways having the highest enrichments, namely carbohydrate metabolism (14.85%), amino acid metabolism (12.87%), lipid metabolism (11.88%), metabolism of cofactors and vitamins (11.88%), xenobiotic biodegradation (9.9%), and metabolism of terpenoids and polyketides (7.92%). CONCLUSION: These findings provide observational evidence of compositional alterations of the gut microbiome and some related metabolites in patients with IT-phase or IA-phase HBV infection. Further studies should investigate whether microbiota modulation can facilitate the progression of CHB and the cause-effect relationship between the gut microbiota and CHB.

Advantages of a Novel Model for Predicting Hepatic Fibrosis in Chronic Hepatitis B Virus Carriers Compared with APRI and FIB-4 Scores.

Background and Aims: Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. Methods: 581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis. Results: In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups. Conclusions: The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.

Effect of liver inflammation on accuracy of FibroScan device in assessing liver fibrosis stage in patients with chronic hepatitis B virus infection.

BACKGROUND: Transient elastography (FibroScan) is a new and non-invasive test, which has been widely recommended by the guidelines of chronic hepatitis B virus (HBV) management for assessing hepatic fibrosis staging. However, some confounders may affect the diagnostic accuracy of the FibroScan device in fibrosis staging. AIM: To evaluate the diagnostic value of the FibroScan device and the effect of hepatic inflammation on the accuracy of FibroScan in assessing the stage of liver fibrosis in patients with HBV infection. METHODS: The data of 416 patients with chronic HBV infection who accepted FibroScan, liver biopsy, clinical, and biological examination were collected from two hospitals retrospectively. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of FibroScan for assessing the stage of liver fibrosis. Any discordance in fibrosis staging by FibroScan and pathological scores was statistically analyzed. Logistic regression and ROC analyses were used to analyze the accuracy of FibroScan in assessing the stage of fibrosis in patients with different degrees of liver inflammation. A non-invasive model was constructed to predict the risk of misdiagnosis of fibrosis stage using FibroScan. RESULTS: In the overall cohort, the optimal diagnostic values of liver stiffness measurement (LSM) using FibroScan for significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4) were 7.3 kPa [area under the curve (AUC) = 0.863], 9.7 kPa (AUC = 0.911), and 11.3 kPa (AUC = 0.918), respectively. The rate of misdiagnosis of fibrosis stage using FibroScan was 34.1% (142/416 patients). The group of patients who showed discordance between fibrosis staging using FibroScan and pathological scores had significantly higher alanine aminotransferase and aspartate aminotransferase levels, and a higher proportion of moderate to severe hepatic inflammation, compared with the group of patients who showed concordance in fibrosis staging between the two methods. Liver inflammation activity over 2 (OR = 3.53) was an independent risk factor for misdiagnosis of fibrosis stage using FibroScan. Patients with liver inflammation activity ≥ 2 showed higher LSM values using FibroScan and higher rates of misdiagnosis of fibrosis stage, whereas the diagnostic performance of FibroScan for different fibrosis stages was significantly lower than that in patients with inflammation activity < 2 (all P < 0.05). A non-invasive prediction model was established to assess the risk of misdiagnosis of fibrosis stage using FibroScan, and the AUC was 0.701. CONCLUSION: Liver inflammation was an independent risk factor affecting the diagnostic accuracy of FibroScan for fibrosis stage. A combination of other related non-invasive factors can predict the risk of misdiagnosis of fibrosis staging using FibroScan.

A novel HBsAg-based model for predicting significant liver fibrosis among Chinese patients with immune-tolerant phase chronic hepatitis B: a multicenter retrospective study.

BACKGROUND: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) in the immune-tolerant (IT) phase is significantly associated with high risk for hepatocellular carcinoma, suggesting requirement for antiviral therapy, particularly for those with histological liver injury. This study aimed to establish a non-invasive panel to assess significant liver fibrosis in IT chronic hepatitis B. PATIENTS AND METHODS: One hundred and thirteen IT-phase CHB patients were retrospectively recruited and divided into two histopathological groups according to their histological profiles: necroinflammatory score <4 (N <4)/fibrosis score ⩽1 (F0-1), and necroinflammatory score ⩾4 (N ⩾4)/fibrosis score ⩾2 (F2-4). Multivariate analysis was conducted to assess the predictive value of the non-invasive model for significant liver fibrosis. RESULTS: IT-phase CHB patients with N <4/F0-1 had significantly higher HBsAg levels than those with N ⩾4/F2-4. The optimal HBsAg level of log 4.44 IU/mL for significant liver fibrosis (F ⩾2) gave an area under the curve (AUC) of 0.83, sensitivity of 81.1%, specificity of 81.6%, positive predictive value (PPV) of 68.2%, and negative predictive value (NPV) of 89.9%. An IT model with HBsAg and gamma glutamyl transpeptidase (GGT) in combination was established, and it had an AUC of 0.86, sensitivity of 86.5%, specificity of 81.6%, PPV of 69.6, NPV of 92.5, and accuracy of 83.2% to predict F ⩾2 in the IT-phase CHB patients. Notably, the IT model exhibited higher predictive value than the existing aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 score, and GGT to platelet ratio. CONCLUSION: The established IT model combining HBsAg and GGT has good performance in predicting significant liver fibrosis in IT-phase CHB patients.

Serum ceruloplasmin can predict liver fibrosis in hepatitis B virus-infected patients.

BACKGROUND: The presence of significant liver fibrosis in hepatitis B virus (HBV)-infected individuals with persistently normal serum alanine aminotransferase (PNALT) levels is a strong indicator for initiating antiviral therapy. Serum ceruloplasmin (CP) is negatively correlated with liver fibrosis in HBV-infected individuals. AIM: To examine the potential value of serum CP and develop a noninvasive index including CP to assess significant fibrosis among HBV-infected individuals with PNALT. METHODS: Two hundred and seventy-five HBV-infected individuals with PNALT were retrospectively evaluated. The association between CP and fibrotic stages was statistically analyzed. A predictive index including CP [Ceruloplasmin hepatitis B virus (CPHBV)] was constructed to predict significant fibrosis and compared to previously reported models. RESULTS: Serum CP had an inverse correlation with liver fibrosis (r = -0.600). Using CP, the areas under the curves (AUCs) to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.774, 0.812, and 0.853, respectively. The CPHBV model was developed using CP, platelets (PLT), and HBsAg levels to predict significant fibrosis. The AUCs of this model to predict significant fibrosis, advanced fibrosis, and cirrhosis were 0.842, 0.920, and 0.904, respectively. CPHBV was superior to previous models like the aspartate aminotransferase (AST)-to-PLT ratio index, Fibrosis-4 score, gamma-glutamyl transpeptidase-to-PLT ratio, Forn's score, and S-index in predicting significant fibrosis in HBV-infected individuals with PNALT. CONCLUSION: CPHBV could accurately predict liver fibrosis in HBV-infected individuals with PNALT. Therefore, CPHBV can be a valuable tool for antiviral treatment decisions.

Novel predictive models using serum ceruloplasmin levels for hepatic steatosis in patients with chronic hepatitis B infection.

AIMS: To evaluate the significance of serum ceruloplasmin (CP) to diagnosis hepatic steatosis (HS) in Chronic hepatitis B (CHB) patients. METHODS: A total of 360 CHB patients with HS (n = 136) or without HS (n = 224) were included. Relationships between CP and HS degrees were analyzed by Spearman rank correlation. HS-predictive models including CP were constructed using multivariate logistic regression analysis and compared to other HS predicting indexes. RESULTS: Serum CP were significantly higher in CHB patients with HS than in patients without HS (P < 0.001) and were positively correlated with HS degree (r = 0.487, P < 0.001). The area under the receiver-operating characteristic curves (AUCs) of using CP to predict HS (S ≥ 1), moderate and severe steatosis (S ≥ 2) and severe steatosis (S = 3) were 0.758, 0.794 and 0.883, respectively. Multivariate analysis showed that CP, age, high density lipoprotein (HDL) and hemoglobin were independent predictors of HS, and CP, body mass index and HDL were independent predictors of moderate and severe HS. Two novel indexes for predicting HS of CHB patients were generated. The AUC of HSCHB-1 (for S ≥ 1) and HSCHB-2 (for S ≥ 2) were 0.881 and 0.916 in the training group, and 0.865 and 0.841 in the validation group, respectively. HSCHB-1 was superior to HS index (P < 0.001), fatty liver disease index (P = 0.0043) and steatosis index of patients with hepatitis B virus infection (P = 0.0029) in predicting HS in CHB patients. CONCLUSIONS: HS of CHB patients was positively associated with serum CP. HSCHB-1 and HSCHB-2 with inclusion of CP are two novel models for predicting HS in CHB patients.

Polycystic kidney and hepatic disease 1 gene mutations in von Meyenburg complexes: Case report.

Von Meyenburg complexes (VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abnormal echographic presentation of the liver. She received magnetic resonance imaging (MRI) examination and liver biopsy, and the results showed she had VMCs. Histologically proved hepatocellular carcinoma was found 1 year after the diagnosis of VMCs. Proband B was a 57-year-old woman with intrahepatic diffuse lesions displayed by abdominal ultrasonography. Her final diagnoses were VMCs, congenital hepatic fibrosis, and hepatitis B surface e antigen-negative chronic hepatitis B after a series of examinations. Then, all the family members of both proband A and proband B were screened for VMCs by MRI or ultrasonography. The results showed that four of the 11 family members from two families, including two males and two females, were diagnosed with VMCs. DNA samples were extracted from the peripheral blood of those 11 individuals of two VMCs pedigrees and subjected to polymerase chain reaction amplification of the polycystic kidney and hepatic disease 1 (PKHD1) gene. Two different mutation loci were identified. Heterozygous mutations located in exon 32 (c.4280delG, p.Gly1427ValfsX6) in family A and exon 28 (c.3118C>T, p.Arg1040Ter) in family B were detected. We speculate that PKHD1 gene mutations may be responsible for the development of VMCs.

A Retrospective Study on the Significance of Liver Biopsy and Hepatitis B Surface Antigen in Chronic Hepatitis B Infection.

To investigate changes in the HBV replication level along with the natural course of chronic HBV infection and to examine the accuracy of the immune tolerant phase defined by the serological profile.A total of 390 chronic HBV-infected patients were retrospectively recruited for this study. They were classified into immune-tolerance (IT), immune-clearance (IC), low-replicative (LR), and HBeAg-negative hepatitis (ENH) phases according to serological profiles (single-standard, SS) or dual-standard (DS) with the inclusion of liver histology. Serum HBV DNA and HBsAg were quantitatively measured, and liver histology was quantitatively analyzed.The accuracy of the SS-defined IT phase was low, and active pathological changes were detected in 56 of 112 SS-defined IT patients. DS-defined IT patients had higher HBsAg levels (P = 0.0002) than the SS-defined patients. The quantitative HBsAg level can help identify SS-defined IT patients with potential liver injury. The area under the received operating characteristic curve for predicting the DS-defined IT phase was 0.831 (HBsAg 4.398 log IU/mL; sensitivity 87.5%; specificity 73.2%). HBV DNA was reduced by 4 logs, whereas HBsAg was only decreased by 2 logs with HBeAg positive to negative phase conversion.Approximately half of IT patients defined by SS may have medium or severe liver injury. Quantitative measurement of the HBsAg level can help identify SS-defined IT patients with potential liver injury.

Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection.

There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the "gold standard" for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians.