Influence of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with HBV-related acute-on-chronic liver failure.

OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) has clinical relevance in patients with acute-on-chronic liver failure (ACLF). We investigated the association between MAFLD and prognosis in patients with ACLF. METHODS: We included patients with ACLF with available clinical data who visited our hospital for nearly 9 years. We compared the prognosis of patients in the different subgroups of ACLF and predicted the incidence of adverse outcomes. Moreover, a new model based on MAFLD was established. RESULTS: Among 339 participants, 75 had MAFLD. The prognosis of patients with ACLF was significantly correlated with MAFLD. Patients with ACLF with concomitant MAFLD tended to have a lower cumulative survival rate (p = 0.026) and a higher incidence of hepatorenal syndrome (9.33% versus 3.40%, p = 0.033) than those without MAFLD. We developed an TIM2 model and the area under the ROC curve of the new model for 30-day and 60-day mortality (0.759 and 0.748) was higher than other predictive methods. CONCLUSION: The presence of MAFLD in patients with HBV-related ACLF was associated with an increased risk of in-hospital mortality. Moreover, The TIM2 model is a high-performance prognostic score for HBV-related ACLF.

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.

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.

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.

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.

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.

Modified model for end-stage liver disease improves short-term prognosis of hepatitis B virus-related acute-on-chronic liver failure.

AIM: To investigate whether the short-term prognosis of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) could be improved by using a modified model for end-stage liver disease (MELD) including serum lactate. METHODS: This clinical study was conducted at the First Affiliated Hospital, Fujian Medicine University, China. From 2009 to 2015, 236 patients diagnosed with HBV-related ACLF at our center were recruited for this 3-month follow-up study. Demographic data and serum lactate levels were collected from the patients. The MELD scores with or without serum lactate levels from survival and non-survival groups were recorded and compared. RESULTS: Two hundred and thirty-six patients with HBV-ACLF were divided into two groups: survival group (S) and non-survival group (NS). Compared with the NS group, the patients in survival the S group had a significantly lower level of serum lactate (3.11 ± 1.98 vs 4.67 ± 2.43, t = 5.43, P < 0.001) and MELD score (23.33 ± 5.42 vs 30.37 ± 6.58, t = 9.01, P = 0.023). Furthermore, serum lactate level was positively correlated with MELD score (r = 0.315, P < 0.001). Therefore, a modified MELD including serum lactate was developed by logistic regression analysis (0.314 × lactate + 0.172 × MELD - 5.923). In predicting 3-month mortality using the MELD-LAC model, the patients from the S group had significantly lower baseline scores (-0.930 ± 1.34) when compared with those from the NS group (0.771 ± 1.32, t = 9.735, P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.859 calculated by using the MELD-LAC model, which was significantly higher than that calculated by using the lactate level (0.790) or MELD alone (0.818). When the cutoff value was set at -0.4741, the sensitivity, specificity, positive predictive value and negative predictive value for predicting short-term mortality were 91.5%, 80.10%, 94.34% and 74.62%, respectively. When the MELD-LAC scores at baseline level were set at -0.5561 and 0.6879, the corresponding mortality rates within three months were 75% and 90%, respectively. CONCLUSION: The short-term prognosis of HBV-related ACLF was improved by using a modified MELD including serum lactate from the present 6-year clinical study.

A hepatic stem cell vaccine is superior to an embryonic stem cell vaccine in the prophylaxis and treatment of murine hepatocarcinoma.

Stem cells and cancer cells express a common subset of antigens called oncofetal antigens. Theoretically, vaccination with stem cells is effective at boosting the preexisting anticancer immune response. Herein we describe the efficacy of two stem cell-based vaccines in the prophylaxis and treatment of subcutaneous hepatic tumors transplanted into mice. C57BL/6j mice were vaccinated weekly with either hepatic stem cells (HSCs) or embryonic stem cells (ESCs) for three weeks, followed by a subcutaneous challenge with Hepa 1-6 cells at one week (group 1) or four weeks (group 2) after vaccination. No tumor formation was observed in HSC-vaccinated mice when challenged within one week after vaccination (group 1), but tumors formed in 10% of mice in the ESC-vaccinated group and in 60% of mice in the unvaccinated group. When the long-term memory response was examined (group 2), only 10% of HSC-vaccinated mice and 20% of ESC-vaccinated mice developed macroscopic hepatocarcinomas compared to 60% of the unvaccinated mice. Besides their function as prophylactic vaccines, administration of either HSC or ESC could be a potential treatment for cancer. In mice with subcutaneous hepatocarcinomas, complete clearance of tumor burden was observed in 80% of mice receiving HSC vaccination, but 40% of ESC-vaccinated mice presented with tumors that did not increase in size over time. These data support that HSC is a superior vaccine candidate for durable antitumor protection in this hepatocarcinoma model.

Ceruloplasmin, a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase.

AIM: To develop a non-invasive model to evaluate significant fibrosis and cirrhosis by investigating the association between serum ceruloplasmin (CP) levels and liver fibrosis in chronic hepatitis B (CHB) patients with normal or minimally raised alanine aminotransferase (ALT). METHODS: Serum samples and liver biopsy were obtained from 193 CHB patients with minimally raised or normal ALT who were randomly divided into a training group (n = 97) and a validation group (n = 96). Liver histology was evaluated by the METAVIR scoring system. Receiver operator characteristic curves were applied to the diagnostic value of CP for measuring liver fibrosis in CHB patients. Spearman rank correlation analyzed the relationship between CP and liver fibrosis. A non-invasive model was set up through multivariate logistic regression analysis. RESULTS: Serum CP levels individualized various fibrosis stages via area under the curve (AUC) values. Multivariate analysis revealed that CP levels were significantly related to liver cirrhosis. Combining CP with serum GGT levels, a CG model was set up to predict significant fibrosis and liver cirrhosis in CHB patients with normal or minimally raised ALT. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value were 0.84, 83.1%, 78.6%, 39.6%, and 96.5% to predict liver cirrhosis, and 0.789, 80.26%, 68.38%, 62.25%, and 84.21% to predict significant fibrosis. This model expressed a higher AUC than FIB-4 (age, ALT, aspartate aminotransferase, platelets) and GP (globulin, platelets) models to predict significant fibrosis (P = 0.019 and 0.022 respectively) and revealed a dramatically greater AUC than FIB-4 (P = 0.033) to predict liver cirrhosis. CONCLUSION: The present study showed that CP was independently and negatively associated with liver fibrosis. Furthermore, we developed a novel promising model (CG), based on routine serum markers, for predicting liver fibrosis in CHB patients with normal or minimally raised ALT.

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.

Treating chronic hepatitis B virus: Chinese physicians' awareness of the 2010 guidelines.

AIM: To investigate Chinese physicians' awareness of the 2010 guidelines on the treatment of chronic hepatitis B virus (HBV) infection. METHODS: This was a quantitative survey that investigated the characteristics and practices of physicians who were treating patients with hepatitis B, the profile of their patients and physician practices regarding the diagnosis and treatment of HBV at the time of the survey. Participants were randomly selected from available databases of Chinese physicians and requested to complete either an online or paper-based survey. Data from the survey responses were analysed. For data validation and interpretation, qualitative indepth interviews were conducted with 39 of the respondents. RESULTS: Five-hundred completed surveys, from 663 physicians were available for analysis. A mean of 175 chronic hepatitis B (CHB) patients was seen by each physician every month, of whom 85 (49%) were treated in line with therapeutic indications stated in the 2010 guidelines. A total of 444 (89%) physicians often (> 60% of the time) adhered to the guidelines. Most physicians used antiviral medications as recommended. For patients with compensated and decompensated cirrhosis, 342 (68%) and 336 (67%) of physicians, respectively, often followed the recommendation to use potent nucleos(t)ide analogues with a high genetic barrier to resistance, using the appropriate treatment more than 60% of the time. Physicians from infectious disease or liver disease departments were better informed than those from gastrointestinal or other departments. CONCLUSION: The majority of Chinese physicians often adhere to Chinese 2010 CHB guidelines and are well-informed about the use of antiviral medications for hepatitis B.

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.

[Validation study of prediction models of hepatitis B virus-related hepatocellular carcinoma].

OBJECTIVE: To validate two previously published models (REACH-B score and CU-HCC score) for predicting the risk of developing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: In-patients of the Liver Center of First Affiliated Hospital Fujian Medical University who tested positive for hepatitis B surface antigen (HBsAg;more than 6 months) and were admitted for treatment between October 1,2004 and May 1,2014 were enrolled for study. The 627 study participants were grouped according to presence of HCC (151 in the HCC case group, and 476 in the non-HCC control group). Relevant clinical data from 3 and 5 years prior to the current hospital admission were collected retrospectively and assessed using the REACH-B and CU-HCC scoring systems. A subset of the study participants (65 HCC cases, and 94 non-HCC controls) was used for the verification analysis of prediction for 5-year risk of HBV-related HCC.T-test, rank sum test, chisquare test and the receiver operating characteristic curve were used for statistical analyses. RESULTS: For the REACH-B score,prediction of 3-year risk of developing HCC had an area under the curve (AUC) of 0.78,a sensitivity of 73.00% and a specificity of 78.70%.In male patients with alanine aminotransferase (ALT) more than or equal to 45 U/L, the REACH-B score prediction of 3-year risk of developing HCC had an AUC of 0.89, a sensitivity of 87.09% and a specificity of 83.86%. The REACH-B score prediction of 5-year risk of HCC had an AUC of 0.79,a sensitivity of 73.60% and a specificity of 75.53%; the CU-HCC score prediction of 5-year risk of HCC had an AUC of 0.76, a sensitivity of 78.40% and a specificity of 77.40%. CONCLUSION: Both the REACH-B and CUHCC scoring systems can be used for HCC prediction among patients at the First Affiliated Hospital Fujian Medical University. For male patients with ALT more than or equal to 45 U/L,the REACH-B score may be a more sensitive predictor for 3-year risk of developing HBV-related HCC.

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.

Serum HBsAg and HBeAg levels are associated with liver pathological stages in the immune clearance phase of hepatitis B virus chronic infection.

The association between hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg) levels and liver inflammation and fibrosis in patients with chronic hepatitis B (CHB) in the immune clearance (IC) remains elusive. The aim of the present study was to investigate whether HBsAg and HBeAg levels were associated with liver inflammation and fibrosis in CHB patients during the IC phase. Kendall's rank correlation analysis and receiver operating characteristic curves were used to determine the correlation between HBsAg, HBeAg and liver pathological stages. Multivariate analysis by forward logistic regression was used to analyze significant predictors of cirrhosis. A liver pathology­predicting model (IC model), which used routinely assessed markers in combination with HBsAg and HBeAg levels, was constructed. There were significantly positive correlations between the HBsAg and HBeAg levels (γ=0.317, P<0.001), and between the HBsAg and HBV­DNA levels (γ=0.489, P<0.001). However, there was no correlation between the HBsAg and alanine aminotransferase levels. HBsAg and HBeAg levels differed significantly at various liver pathological stages and declined progressively in advanced liver pathological stages. Multivariate logistic regression analysis showed that age, HBsAg and HBeAg levels as well as the international normalized ratio (INR) were independent predictors of liver fibrosis during the IC phase. The IC model had a specificity and sensitivity of 88.64 and 78.24%, respectively, a positive predictive value of 48.15% and negative predictive value of 96.79%. In conclusion, HBsAg and HBeAg levels were negatively and indirectly correlated with liver inflammation and fibrosis in CHB patients in the IC phase. The IC model reliably predicted the probability of liver cirrhosis.

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.

A new model for predicting liver cirrhosis in chronic hepatitis B virus carriers with low serum alanine transaminase activity.

OBJECTIVES: To develop a cirrhosis-predicted model in chronic hepatitis B virus carriers with alanine transarninase (ALT) less than two times the upper limit of normal (ULN). METHODS: Treatment-naive patients (n=278), who had undergone liver biopsies, were randomly divided into two groups - a training group and a validation group. Thirteen bio-clinical parameters were analyzed. A liver cirrhosis-predicting model (PPT model) was constructed using multivariate analysis. The diagnostic value of the model was analyzed by the receiving operating characteristics (ROC) method and compared with other available models. RESULTS: A PPT model to predict liver cirrhosis was derived from three independent predictors of liver fibrosis [platelet count (PLT), prothrombin time (PT) and total bile acid (TBA)]. PPT model predicted cirrhosis with an area under the ROC (AUROC) curve of 0.83, a positive predictive value of 86.7% and a negative predictive value of 95.2%. Compared with APRI, FIB-4, age-AST model, AP index and APGA model, PPT model had the highest correlation coefficient (r=0.49) and greater predictive performance (AUROC of 0.83). CONCLUSIONS: The PPT model was accurate in predicting cirrhosis and may reduce the need for liver biopsy in chronic hepatitis B virus carriers with ALT less than two times ULN.