Cirrhosis In Chronic Hepatitis B Patients Research Articles

Machine Learning–Based Models for Advanced Fibrosis and Cirrhosis Diagnosis in Chronic Hepatitis B Patients With Hepatic Steatosis

Background and AimsThe global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants non-invasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. MethodsTreatment-naive CHB patients with concurrent HS who underwent liver biopsy in ten medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from Shapley Additive exPlanations, were compared to Fibrosis-4 Index (FIB-4), Nonalcoholic fatty liver disease Fibrosis Score (NFS), and Aspartate transaminase to platelet ratio index (APRI) using the area under receiver operating characteristic curve (AUROC), and decision curve analysis (DCA). ResultsOf 1,198 eligible patients, the random forest (RF) model achieved AUROCs of 0.778 [95% confidence interval (CI) 0.749-0.807] for diagnosing advanced fibrosis (RF-AF model) and 0.777 (95%CI 0.748-0.806) for diagnosing cirrhosis (RF-C model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the RF-AF model obtained an AUROC of 0.825 (95% CI 0.787-0.862) in patients with HBV DNA ≥105 IU/ml, and RF-C model had an AUROC of 0.828 (95% CI 0.774-0.883) in female patients. The two models outperformed FIB-4, NFS, and APRI in the training cohort, and also performed well in the validation cohort. ConclusionThe RF models provide reliable, non-invasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the co-management of the two diseases.

Evaluating M2BPGi as a Marker for Liver Fibrosis in Patients with Chronic Hepatitis B

BackgroundThe accurate evaluation of liver fibrosis is crucial for the treatment and follow up of chronic hepatitis B (CHB) patients.AimWe examined the efficiency of serum Mac-2 Binding Protein Glycosylation isomer (M2BPGi) in diagnosing liver fibrosis stages in CHB patients.MethodsA cross-sectional study was conducted on 177 adult CHB patients visiting the University Medical Center Ho Chi Minh City, Vietnam between October 2019 and December 2021. M2BPGi, ARFI, APRI, and FIB-4 were tested against FibroScan® for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The optimal M2BPGi cut-off values were identified based on the area under the receiver operating characteristic (AUROC) curve.ResultsThere was a strong agreement between M2BPGi and FibroScan® (r = 0.77, P < 0.001). The optimal M2BPGi cut-off index (C.O.I) for detecting significant fibrosis (F ≥ 2) was 0.79 with an AUROC of 0.77, 67.3% sensitivity, 70% specificity, 60.6% NPV, and 75.3% PPV. Compared with APRI (61%) and FIB-4 (47%), M2BPGi had the greatest sensitivity for diagnosing F ≥ 2. M2BPGi combined with APRI yielded highest diagnosis performance for F ≥ 2 with an AUROC of 0.87. The optimal cut-off index of M2BPGi for diagnosing cirrhosis (F4) was 1.3 with an AUROC of 0.91, 88% sensitivity, 87.4% specificity, 97% NPV, and 61% PPV. The AUROC of M2BPGi for diagnosing F4 was comparable to that of ARFI (0.93).ConclusionsWith cut-off values of 0.79 C.O.I and 1.3 C.O.I, M2BPGi could be an effective method for diagnosing significant fibrosis and cirrhosis in CHB patients, respectively.Graphical

Clinical prediction of HBV-associated cirrhosis using machine learning based on platelet and bile acids

ObjectivesThe present study was conducted to evaluate the performance of serum bile acids in the prediction of cirrhosis in chronic hepatitis B (CHB) population. MethodsDysregulated metabolites were explored using untargeted and targeted metabolomic analyses. A machine learning model based on platelet (PLT) and several bile acids was constructed using light gradient boosting machine (LightGBM), to differentiate HBV-associated cirrhosis (BAC) from CHB patients. ResultsSerum bile acids were dysregulated in BAC compared to CHB patients. The LightGBM model consisted of PLT, TUDCA, UDCA, TLCA, LCA and CA. The model demonstrated a strong discrimination ability in the internal test subset of the training cohort to diagnose BAC from CHB patients (AUC = 0.97). The high diagnostic accuracy of the model was further validated in an independent validation cohort. In addition, the model had high predictive efficacy in discriminating compensated BAC from CHB patients (AUC = 0.89). The performance of the model was better than AST/ALT ratio and the gradient boosting (GB)-based model reported in previous studies. ConclusionsOur study showed that this LightGBM model based on PLT and 5 bile acids has potential in clinical assessments of CHB progression and will be useful for early detection of cirrhosis in CHB patients.

Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response.

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and the Risk of Cirrhosis in Patients with Chronic Hepatitis B-A Retrospective Cohort Study.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is a novel proposed concept that is being recognized worldwide. Both chronic hepatitis B (CHB) and MAFLD have been independently attributed to an increased risk of disease development to cirrhosis. However, it is still unclear whether MAFLD is associated with an increased risk of cirrhosis in CHB patients.AimThis study aimed to analyze the impact of MAFLD on the risk of cirrhosis in CHB patients.MethodsIn this retrospective cohort study, consecutive CHB patients with or without MAFLD were enrolled from January 1st, 2007, to May 1st, 2020, in Guangdong Provincial Hospital of Chinese Medicine. Inverse probability treatment weighting (IPTW) was performed to balance the covariates across groups. The weighted Kaplan–Meier analysis and Cox regression analysis were used to compare both groups for the risk of cirrhosis.ResultsA total of 1223 CHB patients were included in this study during the median follow-up of 5.25 years; of these patients, 355 were CHB-MAFLD patients. After IPTW, the weighted Kaplan–Meier analysis showed that the weighted cumulative incidence of cirrhosis was significantly higher in patients with MAFLD than that in patients without MAFLD (12.6% versus 7.1%, P=0.015). In the weighted multivariate Cox analysis, coexisting MAFLD was related to an increased risk of cirrhosis [adjusted weighted hazard ratio (HR) 1.790; P =0.020]. Age (>40 years, adjusted weighted HR, 1.950; P=0.015), diabetes mellitus (adjusted weighted HR, 1.883; P=0.041), non-antiviral treatment (adjusted weighted HR, 2.037; P=0.013), and baseline serum HBV DNA levels (>2.4 log10 IU/mL, adjusted weighted HR, 1.756; P=0.045) were significant risk factors for cirrhosis.ConclusionWe found that MAFLD was associated with a higher risk of cirrhosis in CHB patients.

Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B.

Objectives We assessed the potential of glial cell line-derived neurotrophic factor (GDNF) as a useful biomarker to predict cirrhosis in chronic hepatitis B (CHB) patients. Methods A total of 735 patients from two medical centers (385 CHB patients and 350 healthy controls) were included to determine the association of serum and tissue GDNF levels with biopsy-proven cirrhosis. The diagnostic accuracy of serum GDNF (sGDNF) was estimated and compared with other indices of cirrhosis. Results We showed significantly higher levels of sGDNF in CHB patients with fibrosis (28.4 pg/ml vs. 11.6 pg/ml in patients without) and patients with cirrhosis (33.8 pg/ml vs. 23.5 pg/ml in patients without). The areas under receiver operating curve (AUROCs) of sGDNF were 0.83 (95% confidence interval (CI): 0.80–0.87) for predicting liver fibrosis and 0.84 (95% CI: 0.79–0.89) for cirrhosis. Findings from the serum protein level and hepatic mRNA expression were consistent. Using the best cutoff to predict cirrhosis, we categorized the patients into sGDNF-high and sGDNF-low groups. The sGDNF-high group had significantly larger Masson's trichrome and reticulin staining-positive area, higher Scheuer score, and METAVIR fibrosis stage (all p < 0.001) but not steatosis. On multivariable regression, sGDNF was independently associated with cirrhosis with an odds ratio of 6.98 (95% CI: 1.10–17.94). Finally, we demonstrated that sGDNF outperformed AST to platelet ratio index, FIB-4, fibroscore, forn index, and fibrometer in differentiating F4 vs. F3. Conclusion Using serum, tissue mRNA, and biopsy data, our study revealed a significant potential of sGDNF as a novel noninvasive biomarker for cirrhosis in CHB patients.

Usefulness of New Shear Wave Elastography Technique forNoninvasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis B: A Prospective Multicenter Study.

To explore the usefulness of liver stiffness measurements (LSMs) by sound touch elastography (STE) and sound touch quantification (STQ) in chronic hepatitis B (CHB) patients for staging fibrosis. This prospective multicenter study recruited normal volunteers and CHB patients between May 2018 and October 2019. The volunteers underwent LSM by STE and supersonic shear imaging (SSI) or by STQ and acoustic radiation force impulse imaging (ARFI). CHB patients underwent liver biopsy and LSM by both STE/STQ. The areas under the receiver operating characteristic curves (AUCs) for staging fibrosis were calculated. Overall, 97 volunteers and 524 CHB patients were finally eligible for the study. The successful STE and STQ measurement rates were both 100 % in volunteers and 99.4 % in CHB patients. The intraclass correlation coefficients (ICCs) for the intra-observer stability of STE and STQ (0.94; 0.90) were similar to those of SSI and ARFI (0.95; 0.87), respectively. STE and STQ showed better accuracy than the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) (AUC: 0.87 vs 0.86 vs 0.73 vs 0.77) in staging cirrhosis. However, both STE and STQ were not superior to APRI and FIB-4 in staging significant fibrosis (AUC: 0.76 vs 0.73 vs 0.70 vs 0.71, all P-values > 0.05). STE and STQ are convenient techniques with a reliable LSM value. They have a similar diagnostic performance and are superior to serum biomarkers in staging cirrhosis in CHB patients.

FibroBox: a novel noninvasive tool for predicting significant liver fibrosis and cirrhosis in HBV infected patients

BackgroundChina is a highly endemic area of chronic hepatitis B (CHB). The accuracy of existed noninvasive biomarkers including TE, APRI and FIB-4 for staging fibrosis is not high enough in Chinese cohort.MethodsUsing liver biopsy as a gold standard, a novel noninvasive indicator was developed using laboratory tests, ultrasound measurements and liver stiffness measurements with machine learning techniques to predict significant fibrosis and cirrhosis in CHB patients in north and east part of China. We retrospectively evaluated the diagnostic performance of the novel indicator named FibroBox, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) in CHB patients from Jilin and Huai’an (training sets) and also in Anhui and Beijing cohorts (validation sets).ResultsOf 1289 eligible HBV patients who had liver histological data, 63.2% had significant fibrosis and 22.5% had cirrhosis. In LASSO logistic regression and filter methods, fibroscan results, platelet count, alanine transaminase (ALT), prothrombin time (PT), type III procollagen aminoterminal peptide (PIIINP), type IV collagen, laminin, hyaluronic acid (HA) and diameter of spleen vein were finally selected as input variables in FibroBox. Consequently, FibroBox was developed of which the area under the receiver operating characteristic curve (AUROC) was significantly higher than that of TE, APRI and FIB-4 to predicting significant fibrosis and cirrhosis. In the Anhui and Beijing cohort, the AUROC of FibroBox was 0.88 (95% CI, 0.72–0.82) and 0.87 (95% CI, 0.83–0.91) for significant fibrosis and 0.87 (95% CI, 0.82–0.92) and 0.90 (95% CI, 0.85–0.94) for cirrhosis. In the validation cohorts, FibroBox accurately diagnosed 81% of significant fibrosis and 84% of cirrhosis.ConclusionsFibroBox has a better performance in predicting liver fibrosis in Chinese cohorts with CHB, which may serve as a feasible alternative to liver biopsy.

Optimizing the Use of the Gamma-Glutamyl Transpeptidase-to-Platelet Ratio and Transient Elastography to Identify Liver Cirrhosis in Patients with Chronic Hepatitis B Concurrent with Nonalcoholic Fatty Liver Disease.

Background and Aim Little information is available about the assessment and optimal use of the gamma-glutamyl transpeptidase-to-platelet ratio (GPR) and transient elastography (TE) in predicting liver cirrhosis in patients with chronic hepatitis B (CHB) and concurrent nonalcoholic fatty liver disease (NAFLD). This study is aimed at comparing their diagnostic performances and developing an optimal approach for predicting liver cirrhosis in CHB patients with NAFLD. Methods Consecutive CHB patients with NAFLD were enrolled. The GPR was calculated, and TE was performed using liver biopsy as a reference standard. The accuracy of predicting liver cirrhosis using GPR and TE was assessed and compared, and an optimal approach was developed. Results Both TE and GPR correlated significantly with the histological fibrosis stage. TE and GPR had excellent performance in predicting liver cirrhosis, and the comparison of areas under the receiver operating characteristic curves revealed that TE was superior to GPR (0.95 vs. 0.85, P = 0.039). Moreover, the dual cutoffs established by the likelihood ratio showed that GPR had a similar misclassification but higher indeterminate rate than TE (54.5% vs. 11.7%, P < 0.001). Additionally, a 2-step approach using GPR followed by TE had comparable performance to that of both GPR and TE tests for all patients (misclassification: 8.9% vs. 8.3%, P = 0.866; indeterminate rate: 15.2% vs. 17.2%, P = 0.750) but could reduce TE scans by approximately one-third. Conclusions Both TE and GPR show excellent performance in predicting liver cirrhosis in CHB patients with NAFLD. The 2-step approach using GPR followed by TE may be optimal for the assessment of cirrhosis in CHB patients with NAFLD.

Effects of Atorvastatin Alongside Conventional Medical Treatment on Liver Fibrosis and Dysfunction in Patients with Chronic Hepatitis B: A Double-Blinded Clinical Trial

Background: Liver fibrosis and related hepatic dysfunction are among major medical issues in patients with chronic hepatitis B (CHB). It finally may lead to cirrhosis, hepatocellular carcinoma (HCC), and liver-related death. Objectives: This study aimed to investigate the effects of adding atorvastatin to the standard antiviral therapy on the hepatic fibrosis and progression of cirrhosis in CHB patients. Methods: In this double-blinded clinical trial, 77 CHB patients referring to the gastroenterology and hepatology clinics in Qom, Iran, were selected by simple random sampling from 2016 to 2017. The participants were randomly divided into an intervention group that received tenofovir (300 mg) with atorvastatin (20 mg) daily and a control group that received tenofovir (300 mg) and placebo of atorvastatin daily. Results: According to the findings, changes in the aspartate aminotransferase (AST) level were not significant in the control (P = 0.771) and intervention (P = 0.266) groups. Changes in the alanine aminotransferase (ALT) level were non-significant in the control group (P = 0.893) but significant in the intervention group (P = 0.018). Changes in the liver fibrosis were significant in the intervention group (P = 0.001) and between the two groups (P < 0.001). Conclusions: According to the study results, adding atorvastatin to the standard antiviral regimen improves the liver function and reduces liver fibrosis in CHB patients. Therefore, it is suggested that atorvastatin be used as complementary therapy.

Transient Elastography and Ultrasonography: Optimal Evaluation of Liver Fibrosis and Cirrhosis in Patients with Chronic Hepatitis B Concurrent with Nonalcoholic Fatty Liver Disease

Background and Aims Concordance between transient elastography (TE) and ultrasonography (US) in assessing liver fibrosis in patients with chronic hepatitis B (CHB) and concurrent nonalcoholic fatty liver disease (NAFLD) has been rarely studied. This study aimed to evaluate the individual and combined performances of TE and US in assessing liver fibrosis and cirrhosis. Patients and Methods Consecutive CHB patients with NAFLD were prospectively enrolled. TE and US examinations were performed, with liver biopsy as a reference standard. Receiver operating characteristic (ROC) curves were obtained to evaluate the diagnostic performance. Differences between the areas under the ROC curves (AUCs) were compared using DeLong's test. Results TE and US scores correlated significantly with the histological fibrosis staging scores. TE was significantly superior to US in the diagnosis of significant fibrosis (AUC, 0.84 vs 0.73; P=0.02), advanced fibrosis (AUC, 0.95 vs 0.76; P<0.001), and cirrhosis (AUC, 0.96 vs 0.71; P<0.001). Combining TE with US did not increase the accuracy of detecting significant fibrosis, advanced cirrhosis, or cirrhosis (P=0.62, P=0.69, and P=0.38, respectively) compared to TE alone. However, TE combined with US significantly increased the positive predictive value for significant fibrosis when compared to TE alone. The optimal cut-off values of TE for predicting advanced fibrosis and cirrhosis were 8.7 kPa and 10.9 kPa, with negative predictive values of 92.4% and 98.7%, respectively. Conclusions TE is useful for predicting hepatic fibrosis and excluding cirrhosis in CHB patients with NAFLD. A combination of TE and US does not improve the accuracy in assessing liver fibrosis or cirrhosis.

Evaluation of eLIFT for Non-invasive Assessment of Liver fibrosis and Cirrhosis in Patients with Chronic Hepatitis B Virus Infection

Recently, the easy Liver Fibrosis Test (eLIFT), a sum of points attributed to age, gender, gamma-glutamyl transpeptidase, aspartate transaminase, platelets, and prothrombin time, was developed for diagnosing advanced fibrosis and cirrhosis in chronic liver disease. We aimed to evaluate the performance of eLIFT to predict liver fibrosis and cirrhosis in patients with chronic hepatitis B (CHB). Histologic and laboratory data of 747 CHB patients were analyzed. The performance of eLIFT for diagnosing liver fibrosis and cirrhosis was compared with that of aspartate transaminase to platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4). To predict advanced fibrosis, the AUROC of eLIFT was comparable with that of APRI (0.66 vs 0.71, p = 0.095) and FIB-4 (0.66 vs 0.67, p = 0.612). To predict severe fibrosis, the AUROC of eLIFT was lower than that of APRI (0.65 vs 0.83, p < 0.001) and FIB-4 (0.65 vs 0.82, p < 0.001). To predict cirrhosis, the AUROC of eLIFT was also lower than that of APRI (0.64 vs 0.85, p = 0.001) and FIB-4 (0.64 vs 0.76, p = 0.033). The eLIFT is not a good non-invasive test for the diagnosis of liver fibrosis and cirrhosis in CHB patients.

Effect of hepatic steatosis on the progression of chronic hepatitis B: A prospective cohort and in vitro study.

AimTo characterize the effect of hepatic steatosis (HS) on the progression of chronic hepatitis B.MethodsA total of 162 chronic hepatitis B (CHB) patients confirmed by liver biopsy were involved in this study. All subjects were prospectively followed-up for 5 years in real-life clinical practice. Fibrosis stage was determined using aspartate aminotransferase-to-platelet ratio index (APRI). The end-point was cirrhosis, liver cancer or death. The effects of steatosis on the biological behavior of hepatocellular carcinoma cells were investigated using oleic acid-induced lipid accumulation in HepG2, HLE, PLC, and SMMC-7721 cells.ResultsMean age, body mass index, and serum cholesterol were significantly higher in CHB patients with HS than those without HS at baseline (p< 0.05). The APRI was lower in patients without HS at baseline (p<0.05). Compared to patients with HS, APRI of patients without HS decreased significantly during the follow-up period (p<0.05). The 5-year cumulative incidence of cirrhosis were 4.17% and 5.19% in patients without and with HS, respectively (p>0.05). The multivariate analysis showed that older (RR 1.07, 95% CI 0.996-1.149, p = 0.065) and S3 stage of liver fibrosis (RR 3.50, 95% CI 0.812–15.117, p=0.093) were risk factors for the progression to cirrhosis. In vitro, cell steatosis promoted proliferation and migration of HCC cells and conferred cell cycle at S phase.ConclusionThe older and S3 stage of fibrosis may be risk factors for progression to cirrhosis in CHB patients with HS. HS may aggravate liver disease, promoting HCC progression.

A Large Scale Validation of Two-Dimensional Shear Wave Elastography in the Diagnosis of Liver Fibrosis Progression in Patients with Chronic Hepatitis B

Two-dimensional shear wave elastography (2D-SWE) is a noninvasive approach for staging chronic liver diseases. Our previous published study had established the cut-off value of 2D-SWE in the diagnosis of significant fibrosis (7.2 kPa), severe fibrosis (9.2 kPa), and cirrhosis (10.4 kPa) based on 304 patients with chronic hepatitis B (CHB). The aim of this study is to validate the value of 2D-SWE in assessing liver fibrosis progression and to compare its diagnostic accuracy with serological fibrosis indices involving aminotransferase/platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), King’s score and Forns index. From July 2015 to January 2017, 639 subjects who underwent partial hepatectomy were enrolled in the study and they were divided into S0–S4 groups by using resected liver specimen. There were 535 males and 104 females with an average age 54.1±10.7 yrs (19-82 yrs). All patients were examined with 2D-SWE (Aixplorer ultrasound system) and serological testing preoperatively to obtain liver stiffness measurements (LSMs) and values of serum fibrosis models. Performance of noninvasive methods was analyzed for validation with areas under the receiver operating characteristic curve (AUCs). Intraobserver agreement of intraclass correlation coefficient was 0.943 for the five measurements of liver stiffness. Mean values of LSMs were 5.52±1.15 kPa (n=33), 6.51±1.09 kPa (n=74), 7.95±0.81 kPa (n=107), 9.41±1.32 kPa (n=135), and 14.55±3.50 kPa (n=290) for the fibrosis S0, S1, S2, S3, and S4 groups, respectively. When the optimal cutoff values of 2D-SWE were applied for S2-4 fibrosis stages, AUCs in predicting significant fibrosis, severe fibrosis and cirrhosis were 0.970, 0.971 and 0.979, respectively. All noninvasive approaches were statistically significantly related to hepatic fibrosis stage (P<0.05). When compared with four serological fibrosis indices, 2D-SWE showed significantly higher AUCs than four serum fibrosis indices in predicting significant fibrosis, severe fibrosis and cirrhosis (P < 0.05 for all). The large scale validation shows that 2D-SWE is an effective approach in predicting significant fibrosis, severe fibrosis, and cirrhosis in CHB patients with notably higher diagnostic accuracy than serum fibrosis models.

Predictive Factors in the Incidence of Cirrhosis in Chronic Hepatitis B Virus Infections.

BackgroundHepatitis B virus (HBV) is among the leading causes of liver cirrhosis worldwide. Predictors of cirrhosis in Iranian chronic hepatitis B (CHB) patients are yet to be clearly identified.ObjectivesEvaluating the predictive factors of liver cirrhosis in CHB.Patients and MethodsA longitudinal study was conducted during 1995 - 2014 on all CHB patients who were referred to Tehran hepatitis center, Tehran, Iran. The patients were assessed during periodic visits through medical history and laboratory data. Logistic regression analyses were used to determine predictors of cirrhosis.ResultsTwo hundred thirty-seven CHB patients were followed for an average duration of 10.6 years, and 41 of these patients developed cirrhosis. The incidence rate of cirrhosis was 2.82/100 person-years. Univariate analyses determined 9 out of 17 factors as significant predictors of outcome in CHB patients. Age of ≥ 45 years, positive hepatitis D virus (HDV), negative HBeAg, platelet count of < 150 (× 109)/L, and HBV DNA level of ≥ 2,000 IU/mL were identified as significant independent predictors of liver cirrhosis in multiple logistic analyses.ConclusionsFive predictive factors that are simple and easy to measure may be used as parameters for the prediction of liver cirrhosis in CHB patients.

Development of algorithms based on serum markers and transient elastography for detecting significant fibrosis and cirrhosis in chronic hepatitis B patients: Significant reduction in liver biopsy.

To develop algorithms for detecting significant fibrosis and cirrhosis in chronic hepatitis B (CHB) patients with the aim of reducing unwarranted liver biopsy. For 307 CHB patients, the aspartate aminotransferase-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), and the result of transient elastography with FibroScan (FS) were obtained when a liver biopsy was carried out. All patients were classified based on APRI or FIB-4 score and further assessed by FS results. Patients who remained unclassified after two steps of evaluation were considered to need liver biopsy. Algorithm implementation found that APRI + FS significantly lowered the requirement for liver biopsy for the detection of significant fibrosis compared to either individual APRI or FS screening (65.1% vs 75.9% or 78.5%, P = 0.003 or <0.001, respectively). The combination of FIB-4 + FS significantly reduced the need for liver biopsy compared to single FIB-4 or FS (58.3% vs 67.4% or 78.5%, P = 0.019 or <0.001, respectively). The FIB-4 + FS algorithm also reduced the need for liver biopsy for detection of significant fibrosis in patients ≥50years old compared to APRI + FS (22.6% vs 56.5%, P <0.001), with a relatively lower accuracy (83.9% vs 98.4%, P = 0.004). Only 3.6% or 1.3% of patients needed liver biopsy for diagnosis of cirrhosis after screening with APRI + FS or FIB-4 + FS, respectively. The APRI + FS and FIB-4 + FS algorithms could significantly reduce the need for liver biopsy with high accuracy, sensitivity, and positive predictive value for diagnosis of significant fibrosis and cirrhosis in CHB patients.

The Gamma-Glutamyl-Transpeptidase to Platelet Ratio Does not Show Advantages than APRI and Fib-4 in Diagnosing Significant Fibrosis and Cirrhosis in Patients With Chronic Hepatitis B: A Retrospective Cohort Study in China.

The gamma-glutamyl-transpeptidase to platelet ratio (GPR) is a new liver fibrosis model, which is reported to be more accurate than aspartate transaminase (AST) to platelet ratio index (APRI) and fibrosis index based on the four factors (Fib-4) for diagnosing significant fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) in West Africa.The aim of this study is to assess the diagnostic accuracy of GPR for significant fibrosis and cirrhosis in Chinese CHB patients, and explore whether GPR deserves to be popularized in China.A total of 372 CHB patients who underwent liver biopsies and routine laboratory tests were retrospectively studied. The Scheuer scoring system was adopted as the pathological standard of liver fibrosis. Using liver histology as a gold standard, the diagnostic accuracies of GPR, APRI, and Fib-4 for significant fibrosis and cirrhosis are evaluated and compared by the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUROCs).Of these 372 patients, 176 (47.3%), 129 (34.7%), and 72 (19.4%) were classified as having significant fibrosis (≥ S2), severe fibrosis (≥ S3), and cirrhosis (S4), respectively. The AUROCs of GPR for significant fibrosis (0.72 vs. 0.78; P = 0.01), severe fibrosis (0.75 vs. 0.80; P = 0.04), and cirrhosis (0.78 vs. 0.83; P = 0.02) were lower than those of APRI. The AUROCs of GPR and Fib-4 for diagnosing significant fibrosis (0.72 vs. 0.70; P = 0.29), severe fibrosis (0.75 vs. 0.73; P = 0.33), and cirrhosis (0.78 vs. 0.75; P = 0.38) were comparable.GPR is a new serum diagnostic model for liver fibrosis and cirrhosis, but does not show advantages than APRI and Fib-4 in identifying significant fibrosis, severe fibrosis, and cirrhosis in CHB patients in China.

A 6 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis B.

Clinical factors and liver biopsy cannot accurately predict the risk of developing cirrhosis in chronic hepatitis B (CHB).This study was to develop a predictive gene signature for cirrhosis in CHB patients. A total of 183 untreated CHB patients were enrolled. GeneChip, significant analysis of microarray (SAM) and prediction analysis of microarray (PAM) were used to select predictor genes (PGs) in liver tissues. The Cirrhosis Risk Score (CRS) was calculated based on 6 PG variables and the predictive value of CRS was evaluated. Firstly differentially expressed genes were filtered from a genome scan and SAM, and 87 significant genes were selected for the signature building. Secondly a signature consisting of 6 PGs (CD24, CXCL6, EHF, ITGBL1, LUM and SOX9) most predictive for cirrhosis risk in CHB patients was developed in the selection set (n=40) by use of PAM and PCR approach. Finally the CRS was calculated to estimate the risk of developing cirrhosis and then tested in validation cohort (n=143). The area under the ROC curves (AUROC) of the CRS was 0.944 and exceeded to 6 PGs and clinical factors. A low CRS cutoff of 6.43 to identify low-risk patients would misclassify only 8.16% of high-risk patients, while a high cutoff of 8.32 to identify high-risk patients would misclassify 0% of low-risk patients. So CRS is a better predictor than clinical factors in differentiating high-risk versus low-risk for cirrhosis and application of CRS in clinical practice could help to reduce the rate of liver biopsy in patients with CHB.

Serum Biomarkers Predictive of Significant Fibrosis and Cirrhosis in Chronic Hepatitis B.

Aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 index are noninvasive biomarkers to evaluate hepatic fibrosis. However, their usefulness in chronic hepatitis B (CHB) patients remains unclear. A total of 631 CHB patients were enrolled and randomly divided into a training set (n=420) and a validation set (n=211). Areas under receiver operating characteristic (AUROC) curves for FIB-4 index and APRI were compared to evaluate their diagnostic values in identifying significant fibrosis and cirrhosis. The AUROC of FIB-4 index for the diagnosis of significant fibrosis and cirrhosis in the entire cohort was higher than that of APRI (0.769 vs. 0.704, P=0.0003 and 0.869 vs. 0.706, P<0.0001). By using cutoff APRI of 0.38 and 4.04 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 67.7% and 76.8%. At cutoff FIB-4 index of 0.87 and 3.40 in the validation set, the diagnostic accuracy for absence of significant fibrosis and presence of cirrhosis was 69.2% and 84.4%. Compared with patients with concordance, patients with overestimated score by FIB-4 index had a significantly higher serum alanine aminotransferase (ALT) level (299±245 vs. 168±196 U/L, P=0.001) as well as a higher ratio of hepatitis flare (ALT>400 U/L) (25% vs. 7.9%, P=0.008). FIB-4 index proves to be more reliable than APRI in predicting significant fibrosis and cirrhosis in CHB patients. By using FIB-4 index, a substantial proportion of patients could be identified correctly as significant fibrosis and cirrhosis without further invasive liver biopsy.

Online combination algorithm for non-invasive assessment of chronic hepatitis B related liver fibrosis and cirrhosis in resource-limited settings

ObjectiveThe use of commercially available noninvasive markers for chronic hepatitis B (CHB) related fibrosis is not widely available in developing countries so clinicians in those countries frequently use free alternatives. We aimed to create an optimized algorithm for selection of patients with the highest probability for presence/absence of significant liver fibrosis and cirrhosis based on the use of multiple free scores. MethodsWe evaluated six free noninvasive markers for CHB related fibrosis against liver biopsy and selected the best thresholds for prediction/exclusion of significant fibrosis and cirrhosis in CHB patients. Algorithm based on four scores and their corresponding thresholds was created. ResultsThe calculator based on developed algorithm can be found at http://www.chb-lfc.com. We evaluated 211 patients in main group and 65 patients in external validation group. We selected four scores for creation of combination algorithm. The algorithm was able to classify 123/211 (58.3%) patients with a 93.5% accuracy of correct classification for prediction of presence/absence of significant fibrosis in main group. In validation group, the algorithm was able to classify 48/65 (73.8%) of patients with 93.8% (45/48) overall accuracy. When used to predict presence/absence of cirrhosis, the algorithm was able to correctly classify 181/211 (85.8%) and 59/65 (90.8%) of patients in main and validation group, respectively, with an overall accuracy of 97.8% and 98.3%, respectively. ConclusionDeveloped algorithm based on routine laboratory tests is a usable, applicable and accurate tool for diagnosis of CHB related fibrosis and cirrhosis, suitable for resource-limited settings where more expensive modalities are unavailable.