Liver Fibrosis in the Natural Course of Chronic Hepatitis B Viral Infection: A Systematic Review with Meta-Analysis.

BACKGROUND: Quantitative data are limited on the natural course of liver fibrosis in patients with chronic HBV infection (CHB). AIMS: To estimate the prevalence of fibrosis status including non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis throughout the natural course of CHB. METHODS: We searched Cochrane library, EMBASE, PubMed, SCOPUS, Web of Science, and ScienceDirect from January 1993 to November 2019 for studies with histologic data on liver fibrosis in CHB natural course. CHB course was defined based on current criteria for identifying infection phases as recommended by international clinical practice guidelines, including the HBeAg-positive immune-tolerant, HBeAg-positive immune-active, HBeAg-negative immune-inactive, HBeAg-negative immune-reactive, and HBsAg-negative phases. Pooled prevalence rate of fibrosis status at each phase was obtained from random-effect meta-analyses. RESULTS: Thirty-three studies with 9,377 adult participants (23.8-49.0 age years; 45.5-88.6% males) were eligible and finally included. The estimated prevalence of non-fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis was, for HBeAg-positive immune-tolerant phase: 31.2% (95%CI 15.6-46.7), 16.9% (95%CI 7.8-26.1), 5.4% (95%CI 0.0-11.2), and 0.0% (95%CI 0.0-1.5); HBeAg-positive immune-active phase: 6.9% (95%CI 3.6-10.2), 50.6% (95%CI 39.2-61.9), 32.1% (95%CI 24.2-40.0), and 12.8% (95%CI 8.6-17.0); HBeAg-negative immune-inactive phase: 32.4% (95%CI 0.0-100.0), 24.8% (95%CI 4.5-45.1), 3.0% (95%CI 0.0-8.3), and 0.0% (95%CI 0.0-1.0); and HBeAg-negative immune-reactive phase: 6.3% (95%CI 3.5-9.2), 50.3% (95%CI 38.9-61.7), 30.3% (95%CI 20.9-39.6), and 10.0% (95%CI 6.6-13.5), respectively. There was only one study for HBsAg-negative phase, thus not allowing further meta-analyses. CONCLUSIONS: Fibrosis risk persists through CHB natural course. These data can support risk estimation in clinical practice and provide reference for noninvasive investigation.

Alanine aminotransferase influencing performances of routine available tests detecting hepatitis B-related cirrhosis.

The performances of routine tests such as FIB-4 and APRI in detecting cirrhosis and significant fibrosis in chronic hepatitis B (CHB) have been shown to be discrepant between studies. Novel tests such as red cell distribution width-platelet ratio (RPR), γ-glutamyl transpeptidase to platelet ratio (GPR) and easy liver fibrosis test (eLIFT) are introduced recently. To evaluate the aminotransferase influence on the performance of these routine tests, a total of 1005 CHB patients who underwent liver biopsies and routine tests were retrospectively analysed. The diagnostic cut-offs referring to likelihood ratio were determined for excluding or including cirrhosis diagnosis and also for ruling in significant fibrosis diagnosis. The performances of RPR, FIB-4, eLIFT and APRI in detecting cirrhosis seemed improved at higher ALT levels, while GPR was conversely impaired. The likelihood ratio was âˆ for APRI cut-off 2 diagnosing cirrhosis in ALT < 2 upper limit of normal (ULN), 14.6 for APRI cut-off 1.5 determining significant fibrosis in ALT ≤ 5ULN and 20.6 for FIB-4 cut-off 3.2 diagnosing ≥ F3 in the total cohort, respectively. The optimal cut-offs for cirrhosis diagnosis were increased with higher ALTs by tests which included aminotransferase, but not for RPR. The proportions of patients classified as having cirrhosis or no cirrhosis stratified by ALT level cut-offs were superior. Stepwise applying RPR, GPR and eLIFT would determine 60% of patients as having cirrhosis or no cirrhosis with an accuracy of 93.0%. In conclusion, the performance of aminotransferase comprising tests in detecting cirrhosis in CHB were influenced by ALT levels. Thus, ALT stratified cut-offs may be a preferred alternative. In resource-limited settings, stepwise applying routine tests could be recommended as a preferred measurement for cirrhosis detection.

Stepwise application of fibrosis index based on four factors, red cell distribution width-platelet ratio, and aspartate aminotransferase-platelet ratio for compensated hepatitis B fibrosis detection.

BACKGROUND AND AIM: Fibrosis index based on four factors (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) were validated with unsatisfactory efficiency. Routine hematology index red cell distribution width-platelet ratio (RPR) had been tried in liver fibrosis detection. This study tries to evaluate the stepwise application of FIB-4, RPR, and APRI in detecting chronic hepatitis B (CHB) fibrosis. METHODS: A total of 246 compensated CHB patients who underwent liver biopsies, transient elastography, and routine blood tests including complete blood count were included. Dual cut-offs were determined to exclude or include cirrhosis diagnosis. Performance of stepwise combining routine biomarkers including RPR, FIB-4, and APRI were statistically analyzed. RESULTS: The Metavir F0, F1, F2, F3, and F4 were identified in 2.4%, 22.0%, 32.1%, 24.0%, and 19.5% of the eligible patients, respectively. The area under receiver operating characteristics curves for detecting significant fibrosis and cirrhosis were 0.853 and 0.883 for transient elastography; 0.719 and 0.807 for FIB-4; 0.638 and 0.791 for RPR; 0.720 and 697 for APRI; and 0.618 and 0.760 for mean platelet volume-platelet ratio, respectively. The proportion of patient determined as cirrhosis or non-cirrhosis was 65.9% by transient elastography, 36.9% by FIB-4, 30.5% by RPR, and 19.5% by APRI, respectively. These numbers for determining significant fibrosis were 49.6%, 24.2%, 21.5%, and 23.6% in the same order. Detected by stepwise application of FIB-4, RPR, and APRI, 41.5% and 52.8% of patients could be determined the state of significant fibrosis and cirrhosis, respectively. CONCLUSIONS: In source-limited settings without transient elastography, stepwise applying FIB-4, RPR, and APRI could free nearly half of CHB patients from liver biopsies in detecting significant fibrosis and cirrhosis.

Optimization of hepatitis B cirrhosis detection by stepwise application of transient elastography and routine biomarkers.

BACKGROUND AND AIM: Significant inflammation may overestimate liver stiffness and result in false positive diagnosis by transient elastography for chronic hepatitis B (CHB) cirrhosis detection. This study tries to further improve the performance by stepwise combination with routine biomarkers. METHODS: A total of 236 compensated CHB patients with alanine transferase lower than five times upper limit of normal, liver biopsies, transient elastography, and routine blood tests were included. Performance of stepwise combination of transient elastography and routine biomarkers was analyzed. RESULTS: The area under the receiver operating characteristics curve for detecting cirrhosis was 0.876 for transient elastography, 0.794 for fibrosis index based on the four factors (FIB-4), 0.765 for age-platelet index (API), 0.715 for aspartate aminotransferase-platelet ratio index (APRI), and 0.661 for alanine-aspartate aminotransferase ratio, respectively. The numbers for significant fibrosis were 0.844, 0.662, 0.595, 0.695, and 0.510 in the same order. The proportion of patients determined as cirrhosis or non-cirrhosis was 66.5% by transient elastography, 41.1% by FIB-4, 14.4% by API, and 24.2% by APRI, respectively; the numbers for significant fibrosis were 55.5% by transient elastography, 11.9% by APRI, and none by the other serum markers. Stepwise combination of transient elastography and FIB-4/APRI increased positive predictive value of confirming cirrhosis diagnosis from 0.677 to 0.808 and 0.724, respectively; and the proportion of patients being determined in the state of cirrhosis and obviating liver biopsy was up to 76%. CONCLUSION: By transient elastography-based stepwise combination with readily available serum markers, performance of detecting compensated CHB cirrhosis could be significantly improved in terms of diagnosis accuracy and proportion of obviating liver biopsy.

Is transient elastography valuable for high-risk esophageal varices prediction in patients with hepatitis-B-related cirrhosis?

BACKGROUND AND AIM: The aim of this study was to evaluate the clinical value of transient elastography (TE) for high-risk esophageal varices (HREV) prediction in hepatitis-B-related cirrhosis patients. METHODS: A total of 238 patients with hepatitis B cirrhosis were prospectively enrolled. All patients had undergone TE and upper gastrointestinal endoscopy. Diagnostic value was assessed by the area under ROC curve (AUROC), predictive value and likelihood ratio. RESULTS: The size of esophageal varices correlated with liver stiffness with Kendall's tau_b 0.236 overall and 0.425 in patients with ALT ≥ 5 × upper limit of normal (ULN). The AUROC of TE predicting HREV was 0.73 (95% confidence interval 0.66-0.80) overall and 0.92 (0.82-1.01) for patients with ALT ≥ 5 × ULN. In patients with ALT ≥ 5 × ULN, cut-off 36.1 kPa predicted HREV with a 100% negative predictive value (NPV), an indefinite negative likelihood ratio (NLR), a 72.7% positive predictive value (PPV) and a positive likelihood ratio (PLR) of 9.3. The AUROC of HREV-predicting model, constructed by ultrasonography and TE (USLS), was 0.84 (0.77-0.90) in the training set and 0.85 (0.76-0.94) in the validating set. Cut-off 3.30 excluded HREV with NPV 0.946 and NLR 0.10, and cut-off 5.98 determined HREV with PPV 0.870 and PLR 10.24. Using USLS, nearly 50% of patients could avoid endoscopic screening. The model's predictive values were maintained at similar accuracy in the validation set. Differences of AUROC in USLS, liver stiffness/spleen diameter to platelet ratio score and ultrasonic score were not significant. CONCLUSIONS: TE may predict HREV in patients with ALT ≥ 5 × ULN. Overall, the clinical values of TE and USLS for HREV prediction should be evaluated by further studies.

Larger biopsies evaluation of transient elastography for detecting advanced fibrosis in patients with compensated chronic hepatitis B.

BACKGROUND AND AIM: Although larger biopsies sample had been recommended for the study of non-invasive liver fibrosis assessment, few studies with larger biopsies for transient elastography (TE) detecting liver fibrosis had been reported. The present study tries to re-evaluate the performance of TE for detecting advanced fibrosis (≥F3) with larger biopsies in patients with compensated chronic hepatitis B. METHODS: A total of 375 compensated patients were analyzed, who had undergone liver biopsy, reliable TE and routine blood tests. RESULTS: The area under the receiver operating characteristic curve (AUC) was influenced by liver biopsy sample: 0.873 (95% confidence interval 0.838-0.909) in total patients, 0.880 (0.844-0.917) in length ≥ 15 mm, 0.897 (0.863-0.932) in length ≥ 20 mm and 0.911 (0.874-0.949) in length ≥ 25 mm. In patients with sample length ≥ 20 mm, the cutoffs to exclude and confirm advanced fibrosis were 7.1 kPa and 12.7 kPa, respectively. Stratified by alanine aminotransferase of two times the upper limit of normal (ALT 2 × ULN), transient elastography detecting advanced fibrosis with the most efficiency by 72.5% of patients obviated from liver biopsy. In patients with normal bilirubin and ALT < 2 × ULN, the area was 0.921 (0.860-0.982), and cutoffs for excluding and confirming diagnosis were 7.4 kPa and 10.6 kPa, respectively; 80% of patients could be classified with or without advanced fibrosis (AF). In patients with normal bilirubin and ALT ≥ 2 × ULN, the corresponding numbers were 0.885 (0.824-0.947), 7.5 kPa, 12.7 kPa and 79.2%, respectively. CONCLUSIONS: Inadequate sample study would underestimate the efficiency of TE on detecting advanced fibrosis. With ALT 2 × ULN stratified cutoffs, TE determined nearly 80% of patients with normal bilirubin as AF or non-AF and obviated them from liver biopsies.

Ultrasonic spleen thickness-based indexes surpass Baveno VI criteria in high-risk gastroesophageal varices detection.

AIMS: To evaluate the efficiency of ultrasonic spleen thickness (UST), routine variables and (expanded) Baveno VI criteria for high-risk gastroesophageal varices (HRGOV) detection in cirrhotic patients. METHODS: In total, 305 cirrhotic patients were retrospectively enrolled in the deriving cohort and 328 cirrhotic patients with hepatitis B sustained viral response were prospectively enrolled in the validation cohort. HRGOV was defined as medium and severe gastroesophageal varices (GOV), mild GOV with red signs or Child-Pugh C. The cut-offs for HRGOV were determined by likelihood ratio indicating strong evidences. Algorithms of Spleen thickness-Age-Liver stiffness measurement (LSM, by Fibroscan®)-Albumin (SALA) and Spleen thickness-Platelet-Albumin (SPA) were derived by multivariate analyses. RESULTS: The area under receiver operating characteristics curve of SALA, SPA, UST, platelet, and LSM were 0.849, 0.835, 0.808, 0.746, and 0.655 in the deriving cohort, and improved to 0.901, 0.904, 0.858, 0.876, and 0.811 in the validation cohort, respectively. While SALA, SPA, UST, platelet, Baveno VI criteria (BVI), and expanded BVI spared 46.6%, 38.0%, 29.2%, 21.0%, 12.1%, and 23.6% esophagogastroduodenoscopy in the deriving cohort, these numbers were improved to 68.1%, 66.8%, 27.1%, 37.8%, 36.0%, and 61.0% in the validating cohort, respectively; however, the negative likelihood ratio of expanded BVI was up to 0.16. SPA spared less esophagogastroduodenoscopy than SALA, which can be supplemented by stepwise applying UST and SPA. Sequentially combining UST and SALA, BVI and SALA exempted additional 10-5% endoscopies. CONCLUSIONS: SPA, without LSM, improves HRGOV detection comparing with BVI. UST based algorithms combination can achieve the best efficiency especially in sustained virus response hepatitis B.

[Transient elastography accurately predicts the severity of disease in patients with chronic hepatitis B].

OBJECTIVE: To evaluate the value of transient elastography (TE) for predicting severity of liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: A total of 969 patients with CHB was enrolled and recruited for analysis, which had been received TE scan, including 258 patients of liver biopsy, and 117 patients of gastric endoscopy. RESULTS: A total of 35 patients was excluded from analysis due to TE failure or unreliable TE. Liver stiffness measurement (LSM) was independently influenced by bilirubin, AST, liver fibrosis and inflammation, ultrasonic score and albumin. TE predicted Child-Pugh C, B/C, liver fibrosis S4, ≥ S3 and ≥ S2 with respective area under receiver operating characteristics curves (AUROC) 0.907 (95%CI 0.886 - 0.928), 0.920(95%CI 0.899 - 0.940), 0.871(95%CI 0.819 - 0.923), 0.852(95%CI 0.805 - 0.899) and 0.807(95%CI 0.749 - 0.865), respectively. While LSM < 32.2 kPa excluded Child-Pugh C with 99.4% probability, LSM ≥ 35.3 kPa determined Child-Pugh B/C with positive predictive value (PPV) 0.820. For compensated CHB, cut-offs of LSM 23.3, 15.2 and 10.8 kPa diagnosed cirrhosis, liver fibrosis ≥ S3 and ≥ S2 with positive likelihood ratio nearly 10.0 and PPV 0.692, 0.882 and 0.980, respectively; and cut-offs 8.8 kPa, 6.6 kPa excluded cirrhosis, liver fibrosis ≥ S3 with negative likelihood ration nearly 0.1 and negative predictive value 0.977 and 0.903, respectively. Correlation coefficient between LSM and grades of esophageal varices was only 0.180, and AUROC for TE predicting EV was of no clinical value. CONCLUSION: TE relatively make accurate prediction in the severity of liver fibrosis and classification of Child-Pugh. Patients with LSM ≥ 10.8 kPa should be considered for receiving antivirus treatment.

Clinical Application of Vibration Controlled Transient Elastography in Patients with Chronic Hepatitis B.

Evaluation of the extent and progression of liver fibrosis and cirrhosis is of critical importance in the management and prognosis of patients with chronic hepatitis B. Due to the limitation of liver biopsy, non-invasive methods, especially liver stiffness measurement (LSM) by vibration controlled transient elastography, have been developed and widely applied for liver fibrosis assessment. LSM aims to reduce, but not to substitute, the need for liver biopsy for fibrosis/cirrhosis diagnosis. While LSM may have potential utility in monitoring treatment response, its applications in prediction of liver complications in terms of portal hypertension and esophageal varices, as well as disease prognosis, have been gradually validated. Here, we review the latest clinical applications of LSM in patients with chronic hepatitis B.

Combining routine markers improves the accuracy of transient elastography for hepatitis B cirrhosis detection.

BACKGROUND AND AIM: Vibration Controlled Transient Elastography (VCTE) is a non-invasive test for liver fibrosis and cirrhosis but may be inaccurate in some patients, especially in those with chronic hepatitis B. This study aims at improving the accuracy of VCTE in cirrhosis detection by combining ultrasound and routine blood parameters. METHODS: Hepatitis B patients with liver biopsies samples ≥20mm underwent VCTE, ultrasound and blood tests, and were divided into training set (n=170) and validation set (n=75). RESULTS: An algorithm consisting of VCTE, international normalization ratio (INR), ultrasonic hepatic vessel and platelet count (CIR-4) and a VCTE-based cirrhosis six-index score (CIR-6) comprised VCTE, INR, platelet, albumin, ultrasonic hepatic vessel and liver parenchyma were derived. In training set, area under receiver operating characteristics curve of CIR-6 and CIR-4 to detect cirrhosis was 0.946 and 0.945, respectively, which was superior to that of VCTE 0.907. CIR-4 could save more liver biopsies. In validation set, CIR-6 detected cirrhosis with accuracy similar to that in training set. However, the sensitivity of CIR-4 and VCTE in validation set lowered to 0.538 and 0.846, respectively. CONCLUSIONS: Combining routine markers improve the accuracy of VCTE for cirrhosis detection in hepatitis B patients. CIR-6 may be more valuable.

Improving transient elastography performance for detecting hepatitis B cirrhosis.

BACKGROUND: Transient elastography is a well-established method for detecting cirrhosis. AIM: To improve the performance of transient elastography in detecting hepatitis B cirrhosis by alanine aminotransferase (ALT)-stratified cutoffs, bilirubin normalization and transient elastography-based algorithms. METHODS: A total of 315 compensated patients were analysed following liver biopsies, transient elastography, ultrasonography and blood tests. RESULTS: The area under the receiver operating characteristics (ROC) curve of transient elastography for predicting cirrhosis was 0.88 (95% confidence interval 0.84-0.92). The cutoffs to exclude and confirm cirrhosis were 10.4 kPa and 17.3 kPa in patients with ALT <5 × upper limit of normal range, 13.7 kPa and 25.0 kPa in ALT ≥5 × upper limit of normal range, respectively. With ALT-stratified cutoffs, 68.6% of patients did not require liver biopsies. Areas under the ROC curve in patients with normal or abnormal bilirubin was 0.90(0.85-0.95) and 0.84(0.77-0.92), respectively. In patients with normal bilirubin, the cutoffs for excluding and confirming cirrhosis were 10.6 kPa and 16.9 kPa, respectively. By transient elastography screening, 78.3% of patients with normal bilirubin would not need a liver biopsy. Areas under the ROC curves between transient elastography and transient elastography-based algorithm including transient elastography-splenomegaly-platelet index [0.90(0.86-0.94)] and ultrasonic score-transient elastography index [0.91(0.86-0.96)] were not significantly different. CONCLUSIONS: Amongst ALT-stratified cutoffs, bilirubin normalization and transient elastography-based algorithm, bilirubin normalization was especially important for improving performance of transient elastography for compensated hepatitis B cirrhosis detection.