Fibrosis Stages F4 Research Articles

Validation of Transient Elastography Cut Points to Assess Advanced Liver Fibrosis in Children and Young Adults: The Boston Children's Hospital Experience

To derive an optimal liver stiffness measurement cut point to discriminate METAVIR fibrosis stage F4 and to validate both METAVIR fibrosis stage F3-F4 and F4 cut points in a separate cohort. Patients at Boston Children's Hospital with liver stiffness measurement from 2006 to 2016 and liver biopsy ≤12 months before screening were eligible. Patients enrolled 2006-2011 were used to calibrate liver stiffness measurement cut points and those enrolled 2011-2016 for validation. Diagnostic performance was assessed by receiver operating curve analysis. In total, 267 subjects were enrolled (97 calibration, 170 validation). The cohorts were similar with 54% male, aged 0-29 years (median 13 years), and liver diseases including 21% autoimmune, 19% viral, 11% nonalcoholic fatty liver, 9% cholestatic, and 9% primary sclerosing cholangitis. Cut points to discriminate F3-F4 and F4 were >8.6 kPa and >11.5 kPa with 81% and 84% accuracy, respectively. Applied to the validation cohort, accuracy was 67% and 75%, respectively. In 44 fasted subjects, the accuracy was 73% and 80%, respectively. This study validates previously determined liver stiffness measurement cut points of 8.6 kPa and 11.5 kPa to predict METAVIR F3-F4 and F4 fibrosis in children and young adults in separate cohorts. With increasing data on the utility and validity of liver stiffness measurement in children, transient elastography may help identify patients with greater risk of advanced fibrosis and those who need liver biopsy assessment and/or surveillance for the complications of cirrhosis in a variety of liver disorders.

DIFFUSE LIVER CHANGES: ASSESSMENT OF ARFI- ELASTOMETRY DIAGNOSTICS EFFICACY

Development of chronic diffuse liver diseases occurs through the progression of fibrosis stages with the final formation of cirrhosis and liver cancer. The "gold standard" for detecting the fibrosis process is a liver biopsy followed by a histological examination of the received material, but it has its drawbacks and contraindications. Recently elastometry is becoming increasingly widespread as it reflects the rigidity of the liver, which is increasing in fibrosis. However, at the moment there is no standard protocol for performing ARFI-elastometry of the liver, which should take into account the choice of topography, the depth of installation of the polling zone, the number of measurements of the shear wave. Objectives of the study: standardization of the procedure for performing ARFI-elastometry of the liver for further evaluation of the fibrosis stages; detection of the most sensitive echographic changes in the liver at various stages of fibrosis. Based on healthy volunteers examinations, a standardized protocol for patients with diffuse liver changes was developed. While using shear wave elastography, it was noted that detected number of echographic symptoms corresponds to the elastometry stage of fibrosis not in all cases. During the study, it was determined that in the F1 and F2 stages of fibrosis, 1 to 4 echographic symptoms occurred in patients; in F3 and F4 fibrosis stages — from 3 to 11 echographic symptoms accordingly. It is noted that with an increase in the fibrosis stage, the number of echographic symptoms is basically increases, too. A special group of patients without obvious echographic symp- toms, but with verified F2-F4 fibrosis stages was selected using elastometry. In this group, echographic symptoms were not detected in 42% of cases with verified F2-F4 fibrosis. In 10% of cases with F3 and F4 fibrosis stages there were only 1–2 echographic symptoms. Thus, the detection of at least a single echographic symptom in the patient should be the warning sign of possible presence of fibrosis or cirrhosis.

Diagnosis of Liver Fibrosis With Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA-M2BP) Among Chronic Hepatitis B Patients.

BackgroundWisteria floribunda agglutinin-positive Mac-2 binding protein (WFA-M2BP) is a protein with altered glycosylation that reacts with lectin, and was recently identified as a useful non-invasive biomarker for the diagnosis of liver fibrosis in patients with hepatitis C virus infection.This study aimed to evaluate the diagnostic efficacy of WFA-M2BP for liver fibrosis in the context of hepatitis B virus (HBV).MethodsWe enrolled 151 patients infected with HBV. Liver biopsy and elastography (Fibroscan) were performed during the initial visit. Fibrosis was graded according to the Knodell histologic activity index (F0–3). WFA-M2BP levels were determined with an automated immunoassay analyzer (M2BPGi, HISCL-5000, Sysmex, Japan). The diagnostic efficacy of WFA-M2BP was compared with those of various conventional or composite biomarkers, including enhanced liver fibrosis (ELF) score, Fibroscan, aspartate transaminase (AST)-to-platelet ratio index (APRI), and FIB-4, based on the area under the ROC curve (AUC) value.ResultsThe majority of patients were at fibrosis stages F1 and F2. The F2 and F3 AUC values for WFA-M2BP were similar to those for FIB-4, APRI, ELF, and Fibroscan, although the latter showed the best diagnostic efficacy. The diagnostic accuracy of all tested biomarkers for F2 and F3 was 60–70%. In multivariate analysis, WFA-M2BP, ELF, and platelet count significantly predicted stage ≥F2, whereas only platelet count significantly predicted F3.ConclusionsWFA-M2BP can support a diagnosis of liver fibrosis with similar diagnostic efficacy to other biomarkers, and predicted liver fibrosis stage ≥2 among patients with chronic hepatitis B.

PET/CT with 18F Fluorocholine as an Imaging Biomarker for Chronic Liver Disease: A Preliminary Radiopathologic Correspondence Study in Patients with Liver Cancer.

Purpose To determine the relationship between hepatic uptake at preoperative fluorine 18 (18F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. Materials and Methods Forty-eight patients with resectable liver tumors underwent preoperative 18F fluorocholine PET/CT. Mean liver standardized uptake value (SUVmean) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUVmean were examined with analysis of variance. Results Liver SUVmean ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = -0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUVmean also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for 18F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. Conclusion Correlations found in patients undergoing hepatic resection for liver cancer between liver 18F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of 18F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. © RSNA, 2018.

Association between Presence of Esophageal Varices on Endoscopy and Extreme Degree of F4-Stage Fibrosis on Fibroscan in HCV-Related Chronic Liver Disease

Background: Hepatitis C Virus (HCV) infection is one of the causes which cause liver fibrosis, cirrhosis and carcinoma if left untreated. Patients who present with acute HCV infection, 50-70% of them develop chronic infection. This study attempted to see an association between F4 fibrosis in liver on fibroscan and esophageal varices on endoscopy in HCV related chronic liver disease (CLD) patients. Method: This study was conducted in Gastroenterology and Hepatology division of holy family hospital, Rawalpindi. Total 117 patients of 10 to 90 years were included. All patients were having HCV related CLD. Patients having F4 fibrosis stage were included while patients having fibrosis stage up to F3 fibrosis stage were excluded. All data regarding age, gender, F4 fibrosis and esophageal varices was entered and analyzed using the statistical package of social sciences while descriptive analysis was performed. Results: Amongst 114 patients who presented with F4 fibrosis stage on fibroscan 69.3% (79) of them were diagnosed for esophageal varices on endoscopy and 30.7% (35) were not having esophageal varices on endoscopy. Patients who were having esophageal varices on endoscopy 84.5% (49) of them were males and 55.9% (33) were females. Study participants having F4 fibrosis stage, 98.3% of them were males and 96.6% were females. So, there was not much difference between males and females having an extreme degree of fibrosis on fibroscan. Conclusion: Patients who were having F4 fibrosis stage on fibroscan, 2/3 of them were having esophageal varices on endoscopy. Esophageal varices were more present in males as compared to females.

Clinical Evaluation of Hepatocarcinogenesis and Outcome Using a Novel Glycobiomarker Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA+-M2BP) in Chronic Hepatitis C with Advanced Fibrosis.

This study aimed to assess the association between the serum glycobiomarker Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) for liver fibrosis and outcomes and carcinogenesis of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients with advanced fibrosis. Serum WFA+-M2BP levels were measured in 128 consecutive CHC patients including 49 with HCC histopathologically diagnosed with advanced fibrosis (44 with fibrosis stage F3 and 84 with fibrosis stage F4) in our hospital. The median WFA+-M2BP level was significantly higher in F4 than in F3 patients (6.9 vs. 2.3 cutoff index [COI], respectively; p<0.001). The difference in WFA+-M2BP levels between patients with and without HCC was not significant. The respective 5-/8-yr survival rates of patients without HCC at enrollment with high (≥4 COI, n=39), intermediate (1-4 COI, n=33), and low WFA+-M2BP (<1 COI, n=7) levels were 78%/48%, 100%/82%, and 100%/100%, respectively. The differences in survival rates between groups were significant (p=0.0041). Patients with high WFA+-M2BP levels had a significantly higher incidence of HCC than those with low WFA+-M2BP levels (p=0.0019). Cumulative 5-yr carcinogenesis rates in patients with high, intermediate, and low WFA+-M2BP levels were 48.7%, 16.9%, and 0%, respectively; the differences between groups were significant (p=0.002). Serum WFA+-M2BP levels might allow the prediction of carcinogenesis and outcome in CHC patients with advanced fibrosis.

Liver Fibrosis: Deep Convolutional Neural Network for Staging by Using Gadoxetic Acid-enhanced Hepatobiliary Phase MR Images.

Purpose To investigate the performance of a deep convolutional neural network (DCNN) model in the staging of liver fibrosis using gadoxetic acid-enhanced hepatobiliary phase magnetic resonance (MR) imaging. Materials and Methods This retrospective study included patients for whom input data (hepatobiliary phase MR images, static magnetic field of the imaging unit, and hepatitis B and C virus testing results available, either positive or negative) and reference standard data (liver fibrosis stage evaluated from biopsy or surgical specimens obtained within 6 months of the MR examinations) were available were assigned to the training (534 patients) or the test (100 patients) group. For the training group (54, 53, 81, 113, and 233 patients with fibrosis stages F0, F1, F2, F3, and F4, respectively; mean patient age, 67.4 ± 9.7 years; 388 men and 146 women), MR images with three different section levels were augmented 90-fold (rotated, parallel-shifted, brightness-changed and contrast-changed images were generated; a total of 144 180 images). Supervised training was performed by using the DCNN model to minimize the difference between the output data (fibrosis score obtained through deep learning [FDL score]) and liver fibrosis stage. The performance of the DCNN model was evaluated in the test group (10, 10, 15, 20, and 45 patients with fibrosis stages F0, F1, F2, F3, and F4, respectively; mean patient age, 66.8 years ± 10.7; 71 male patients and 29 female patients) with receiver operating characteristic (ROC) analyses. Results The FDL score was correlated significantly with fibrosis stage (Spearman rank correlation coefficient: 0.63; P < .001). Fibrosis stages F4, F3, and F2 were diagnosed with areas under the ROC curve of 0.84, 0.84, and 0.85, respectively. Conclusion The DCNN model exhibited a high diagnostic performance in the staging of liver fibrosis. © RSNA, 2017 Online supplemental material is available for this article.

Efficacy and safety of sofosbuvir-based therapies in patients with advanced liver disease in a real-life cohort.

BackgroundThe combination of sofosbuvir (SOF) with ribavirin (RBV) or daclatasvir (DCV) or simeprevir (SIM) for the treatment of patients infected by chronic hepatitis C (CHC) have led to significantly increased rates of sustained virological response (SVR). However, there is only limited data regarding factors associated with treatment failure in a “real-life” cohort.Patients and methodsConsecutive treatment-naive and treatment-experienced patients F3–F4 were treated with SOF-based interferon-free therapy in our hospital from November 2013 to July 2015. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after cessation of therapy (SVR12).ResultsA total of 167 treatment-naive and 207 treatment-experienced patients were treated and followed up for 2 years (n=383). Overall, 71% were men; among them, 54% had cirrhosis and the median age was 53 years. SVR12 was achieved by 82% of the patients receiving SOF+RBV, 92% receiving SOF+DCV, and 79% receiving SOF+SIM. Metavir F4 and albumin serum were found as independent risk factors associated with treatment failure in groups receiving SOF+RBV (p=0.008 and p=0.001), SOF+DCV (p=0.038 and p=0.043), and SOF+SIM±RBV (p=0.014 and p=0.017), respectively. The most common adverse events were fatigue, nausea, headache, and anemia. Three patients discontinued the treatment due to an adverse event.ConclusionThese findings suggest that 12-week SOF-based regimen plus RBV or DCV or SIM is an efficacious and well-tolerated treatment in CHC patients with fibrosis stage F3–F4. Patients, who display risk factors for cirrhosis, should be referred to an experienced viral hepatitis center.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in chronic hepatitis C patients

Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has recently been developed as a promising liver fibrosis glyco biomarker. We assessed its efficacy in evaluating liver disease severity in chronic hepatitis C (CHC) in Taiwan. The association between WFA+-M2BP and histological features was evaluated among those CHC patients underwent liver biopsy. We also aimed to clarify the factors determining the performance of WFA+-M2BP in CHC. A total of 229 CHC patients were consecutively recruited. The mean value of WFA+-M2BP in patients from F0 to F4 was 1.68, 2.23, 3.45, 3.48, 3.77 respectively (linear trend P = 0.008). Linear regression analysis revealed that alanine aminotransferase (odds ratio [OR]: 0.03, 95% confidence intervals [CI]: 0.02–0.05, P < 0.001), AST (OR: −0.1, 95% CI: −0.02 to −0.01, P < 0.001), and liver fibrosis (OR: 0.30, 95% CI: 0.01–0.59, P = 0.043) were the independent factors correlated to serum WFA+-M2BP level. The optimal cutoff values of WFA+-M2BP for fibrosis stages F1, F2, F3, and F4 were 1.42, 1.61, 1.42, and 2.67, respectively. Multivariate analysis revealed that the platelet count (OR/CI: −0.009/0.986–0.996, P = <0.001), r-glutamyl transferase (OR/CI: 0.007/1.000–1.013, P = 0.036), and WFA+-M2BP (OR/CI: 0.187/1.057–1.374, P = 0.005). We concluded that WFA+-M2BP is a competent noninvasive marker for liver fibrosis assessment in CHC patients.

Hepatic stellate cells secreting WFA+ -M2BP: Its role in biological interactions with Kupffer cells.

Hepatic stellate cells (HSCs) play a central role in hepatic fibrosis and are regulated by Kupffer cells (KCs). Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) was recently identified as a serum marker for hepatic fibrosis. Although WFA+ -M2BP was identified as a ligand of Mac-2, the function of WFA+ -M2BP in hepatic fibrosis remains unclear. Liver specimens were obtained from five patients with cirrhosis, five with chronic hepatitis, and five without hepatic fibrosis. WFA+ -M2BP kinetics were evaluated histologically and in subpopulations of liver cells such as HSCs, KCs, endothelial cells, biliary epithelial cells, and hepatocytes in in vitro culture. The function of WFA+ -M2BP in activated HSCs was evaluated using immunoblot analysis. Numbers of WFA+ -M2BP-positive cells in liver tissues increased with fibrosis stage. There were significant differences in WFA+ -M2BP levels between fibrosis stages F0 and F1-2 (P=0.012) and between fibrosis stages F1-2 and F3-4 (P<0.001). HSCs were the source of WFA+ -M2BP secretion in in vitro cultures of liver cells, as determined by sandwich immunoassay. Cells of the human HSC line LX-2 also secreted WFA+ -M2BP. Histologically, tissue sections showed that WFA+ -M2BP was located in Mac-2-expressing KCs. In vitro assays showed that exogenous WFA+ -M2BP stimulation enhanced Mac-2 expression in KCs and that HSCs co-cultured with KCs increased α-smooth muscle actin expression. Finally, Mac-2-depleted KCs with short interfering RNA had reduced α-smooth muscle actin expression following co-culturing with HSCs. WFA+ -M2BP from HSCs induces Mac-2 expression in KCs, which in turn activates HSCs to be fibrogenic.

Ruling-in and Ruling-out Significant Fibrosis and Cirrhosis in Patients with Chronic Hepatitis C Using a Shear Wave Measurement Method.

To prospectively assess the cutoff values of a point shear wave measurement (SWM) method for ruling-in and ruling-out significant fibrosis and cirrhosis using transient elastography (TE) as the reference standard. Consecutive patients with chronic hepatitis C were enrolled. Liver stiffness was assessed with the SWM method implemented on the HI VISION Ascendus ultrasound system (Hitachi Ltd, Japan) and with the TE method of the FibroScan® device (Echosens, France). For staging significant fibrosis (F>/=2) and cirrhosis (F=4) we used the TE cutoffs of 7.0 and 12.0 kiloPascal (kPa), respectively. The diagnostic performance of SWM was assessed by calculating the area under the receiver operating characteristic (AUROC) curve. Cutoffs with specificity or sensitivity > 90% were chosen to rule-in or rule-out F>/=2 and F=4. 445 individuals [235 males, 210 females; mean age, 61.1 (13.3) years] were studied: 190 (42.7%) individuals had F0-F1 fibrosis stage, 82 (18.4%) F2, 46 (10.3%) F3, and 127 (28.6%) F4 fibrosis stage. For ruling-in F>/=2 the SWM cutoff was 6.78 kPa [sensitivity, 76.9%(70.6-82.4); specificity, 90.3% (85.0-94.3)] and for ruling-out it was 5.55 kPa [sensitivity, 90.6% (85.8-94.1); specificity, 72.2% (64.9-78.6)]. For ruling-in F=4 the SWM cutoff was 9.15 kPa [sensitivity, 83.3% (74.4-90.2); specificity, 90.1% (86.0-93.2)] and for ruling-out it was 8.41 kPa [sensitivity, 90.6% (82.9-95.6); specificity, 82.2% (77.3-86.4)]. AUROCs were 0.92 (0.89-0.94) for F>/=2 and 0.94 (0.91-0.96) for F=4. In clinical practice, the use of a dual cutoff of SWM may increase the confidence in staging liver fibrosis with a non-invasive shear wave elastography technique.

Evaluation of splenic perfusion and spleen size using dynamic computed tomography: Usefulness in assessing degree of liver fibrosis

To enhance the usefulness of splenic perfusion evaluated by means of dynamic computed tomography (CT) and spleen size in assessing the degree of liver fibrosis. We retrospectively studied 133 patients who had undergone dynamic CT before hepatectomy. Fibrosis was histologically established in all. First we calculated splenic perfusion parameters K1 (inflow rate constant), 1/k2 (mean transit time; MTT), and K1 /k2 (distribution volume; Vd ), using compartment model analysis. Then we compared the stage of fibrosis with splenic perfusion and spleen size (long axis, R), using the Kruskal-Wallis test and multiple comparisons. After that, we assessed the diagnostic accuracy of the combination of splenic perfusion, spleen size, age, gender, and the presence or absence of hepatitis B and hepatitis C viral infection in detecting liver fibrosis, using stepwise regression and receiver operating characteristic analysis. Significant differences (P <0.05) in MTT were observed in comparisons between fibrosis stages F0 and F4, between F1 and F4, and between F2 and F4. Significant differences (P <0.05) in R were observed in comparisons between F0 and F4, and between F1 and F4. Considering the presence or absence of hepatitis B and C viral infection along with MTT and R, the areas under the receiver operating characteristic curves were 0.89 for ≥F1, 0.83 for ≥F2, 0.82 for ≥F3, and 0.82 for F4. Splenic MTT and spleen size are helpful in assessing liver fibrosis.

The inverse effect of meal intake on controlled attenuation parameter and liver stiffness as assessed by transient elastography

BackgroundControlled attenuation parameter (CAP) and liver stiffness (LS) measured by transient elastography (TE, Fibroscan®) have been used for steatosis and fibrosis assessment. We evaluated the effect of meal intake on CAP and LS values.MethodsForty patients who had had a liver biopsy within the previous month were recruited. The biopsy was graded for fibrosis (F) and steatosis (S) stagings. TE was performed after overnight fasting (baseline values) and 15, 30, 45, 60, 90, and 120 min following the intake of a standard commercial formula meal, and every 30 min until LS and CAP values returned to baseline. The effect of meal intake on CAP and LS values was analyzed with a multilevel mixed model approach.ResultsThe mean age was 53.1 ± 11.2 years old. The mean (SD) BMI was 25.6 ± 4.5 kg/m2. F0, F1, F2, F3 and F4 fibrosis stages were found in 17 (42.5%), 9 (22.5%), 4 (10.0%), 8 (20.0%) and 2 (5.0%), respectively. S0, S1, S2 and S3 steatosis stages were seen in 22 (55.0%), 11 (27.5%), 4 (10.0%) and 3 (7.5%), respectively. The mean (SD) CAP and median (IQR) LS values at baseline were 249.7 ± 58.1 dB/m and 11.9 (6–18.1) kPa. A significant decrease in CAP values was observed in all patients 15 to 120 min after meals, with the CAP peak value at 60 min and the mean post-meal delta reduction of 18.1 dB/min. CAP values declined after meals at early fibrosis stages and across all stages of steatosis. A significant increase in LS values after meal intake was observed within 15 to 120 min, with the LS peak value at 15 min and the mean post-meal delta increase of 2.4 kPa. Post-meal CAP and LS values returned to baseline within 150 min following meals.ConclusionFollowing a meal, patients’ CAP values declined with the peak value at 60 min, contrasting with the rising of LS values with the peak value at 15 min. The post-meal CAP and LS values returned to baseline by 150 min. A fasting period of more than 150 min after a meal is recommended for patients undergoing TE.

Correlation of liver stiffness measured by FibroTouch and FibroScan with Ishak fibrosis score in patients with chronic hepatitis B

Objective: To investigate the correlation of liver stiffness measured by FibroTouch (FT) and FibroScan (FS) with Ishak fibrosis score in patients with chronic hepatitis B. Methods: A total of 313 patients with chronic hepatitis B who visited Department of Liver Cirrhosis in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from November 2014 to May 2016 were enrolled. All the patients underwent liver biopsy, and FT and FS were used to determine liver stiffness measurement (LSM). Serum biochemical parameters were measured, and the aspartate aminotransferase-to-platelet ratio index (APRI) in a multi-parameter model of liver fibrosis and fibrosis-4 (FIB-4) index were calculated. The consistency between the results of four noninvasive examinations and Ishak fibrosis score was compared. The t-test was used for comparison of LSM determined by FT and FS. Pearson correlation analysis was used investigate the correlation between LSM determined by FT and FS; Spearman correlation analysis was used to investigate the correlation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and Knodell score with LSM determined by FT and FS; the correlation between LSM determined by FT and FS and fibrosis stage was analyzed by partial correlation analysis adjusted by Knodell score for liver inflammatory activity; Spearman correlation analysis was used for APRI, FIB-4, and fibrosis stage. Based on the Ishak fibrosis score, the receiver operating characteristic (ROC) curve was used to analyze the values of four noninvasive methods in the diagnosis of liver fibrosis. Results: There was no significant difference in LSM measured by FT and FS in all patients (15.75±9.42 kPa vs 15.42±10.52 kPa, P > 0.05) and Pearson correlation analysis indicated a significant positive correlation between them (r = 0.858, P < 0.01); serum ALT and AST levels and liver inflammatory activity were correlated with LSM determined by FT and FS. There was a significant positive correlation between LSM determined by FT and FS and fibrosis stage (r = 0.501 and 0.526, both P < 0.001), and APRI and FIB-4 were also positively correlated with fibrosis stage (r = 0.236 and 0.218, both P < 0.001). Based on the Ishak fibrosis score, in the diagnosis of fibrosis stages F3, F4, F5, and F6, the areas under the ROC curve were 0.915/0.856/0.839/0.816 for FT, 0.933/0.883/0.849/0.856 for FS, 0.618/0.630/0.608/0.638 for APRI, and 0.614/0.624/0.595/0.649 for FIB-4, and FT and FS had a significantly larger areas under the ROC curve than APRI and FIB-4. Conclusion: LSM determined by FT or FS has a good correlation with the Ishak fibrosis score, so FT and FS have a significantly better diagnostic performance for liver fibrosis than APRI and FIB-4.

Transient Elastography for Diagnosis of Stages of Hepatic Fibrosis and Cirrhosis in People with Alcoholic Liver Disease

The presence and progression of hepatic (liver) fibrosis into cirrhosis is a prognostic variable having impact on survival in people with alcoholic liver disease. Transient elastography (TE) is a non-invasive method for assessing and staging hepatic fibrosis. To determine the diagnostic accuracy of TE for diagnosis and staging hepatic fibrosis in people with alcoholic liver disease when compared with liver biopsy (LB). Diagnostic cohort and diagnostic case-control study designs that assessed hepatic fibrosis in participants with alcoholic liver disease with TE and LB, irrespective of language or publication status. We followed the guidelines in the draft Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. Five retrospective and nine prospective cohort studies with 834 participants provided data for the review analyses. We performed an HSROC analysis and reported an SROC curve for hepatic fibrosis stage F4 (cirrhosis). The HSROC analysis suggested that when the cut-off value changes, there is a wide variation in specificity and a more limited variation in sensitivity. We performed an additional analysis with the studies with the most commonly used cut-off value of 12.5 kPa. The summary sensitivity and specificity of TE (seven studies with 330 participants) were 0.95 and 0.71 with LR+ 3.3 and LR- 0.07. TE may be used as a diagnostic method to rule out liver cirrhosis(F4) in people with alcoholic liver disease when the pre-test probability is about 51% (range 15% to 79%). TE may also help in ruling out severe fibrosis (F3 or worse). LB investigation remains an option if the certainty to rule in or rule out the stage of hepatic fibrosis or cirrhosis remains insufficient after a clinical follow-up or any other non-invasive test considered useful by the clinician.

High fasting insulin concentrations may be a pivotal predictor for the severity of hepatic fibrosis beyond the glycemic status in non-alcoholic fatty liver disease patients before development of diabetes mellitus.

Insulin resistance and type 2 diabetes mellitus (T2DM) contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolic factors and the histological severity in NAFLD patients before development of T2DM is not well known. In 103 biopsy-proven NAFLD patients (68 men and 35 women) with hemoglobin A1c of <6.5% and fasting blood glucose of <126mg/dL, we investigated whether glucose metabolic factors influenced the severity of hepatic fibrosis without prior known T2DM. Female gender, age, serum aspartate aminotransferase, the aspartate aminotransferase/alanine aminotransferase ratio, fasting immunoreactive insulin (f-IRI), homeostasis model assessment - insulin resistance, hemoglobin A1c, hyaluronic acid, and type IV collagen 7s were significantly higher, and 1,5-anhydroglucitol was significantly lower, in the fibrosis stage F3 group than in the F0-2 group. Multiple logistic regression analysis showed that only f-IRI (P = 0.006; odds ratio, 1.15151; 95% confidence interval, 1.04198-1.27254) was significantly indicated as a predictive factor for F3. As determined by both forward and backward stepwise selection analyses to optimize the model, f-IRI (P = 0001; odds ratio, 1.16788) remained an independent predictive factor for F3. To discriminate the F3 group from the F0-2 group, the area under the receiver operating characteristic curves showed that fasting insulin was 0.7219, and the best cut-off value of f-IRI was 13.2μU/mL in the receiver operating characteristic curve analysis. High fasting insulin concentrations may be a pivotal glucose metabolic predictor for the severity of hepatic fibrosis beyond the glycemic status in NAFLD patients before development of T2DM.

Visual morphometry and three non-invasive markers in the evaluation of liver fibrosis in chronic liver disease

Objective: Liver fibrosis is traditionally graded into categorical stages with cirrhosis as the highest stage. However, cirrhosis stage may vary between individuals widely in terms of the amount of fibrosis which is not assessed by traditional staging systems. We aimed to utilise visual morphometry to quantify the amount of fibrosis in liver biopsy and compare how non-invasive methods of quantifying liver fibrosis correlated with histological measures.Materials and methods: Liver biopsy specimens from 115 consecutive chronic liver disease patients were assessed by a single pathologist for fibrosis stage by the Clinical Research Network and METAVIR systems as well as percentage fibrosis by visual morphometry. Liver T1 relaxation times, liver stiffness measurement (LSM) by transient elastography and enhanced liver fibrosis (ELF) score were compared between fibrosis stages. In addition, these parameters were correlated with pathologist’s visual estimate of percentage fibrosis and their predictive ability for advanced fibrosis and cirrhosis assessed by area under receiver operating curve (AUROC).Results: All four parameters increased sequentially from fibrosis stage F0 to F4 (p<.001 for each). AUROCs for advanced fibrosis and cirrhosis were 0.931 and 1.000 respectively for pathologist’s estimate of fibrosis, 0.707 and 0.926 for ELF score, 0.763 and 0.972 for T1 and 0.881 and 0.989 for LSM. LSM, ELF score and T1 correlated significantly with pathologist’s estimate of percentage fibrosis.Conclusion: Non-invasive markers of fibrosis LSM, ELF and T1 relaxation time provide continuous surrogates for categorical histopathological staging of fibrosis which can be useful as markers of progression and regression of fibrosis on follow-up.

Adaptation of liver stiffness measurement depth in bariatric surgery candidates with suspected nonalcoholic fatty liver disease.

A thick layer of subcutaneous adipose tissue may lead to an overestimation of liver stiffness by transient elastography. The aim of this study was to assess whether liver stiffness measurement (LSM) was overestimated using an XL probe in patients with severe obesity and, if so, to reprocess the data to the adapted depth to obtain the appropriate LSM (LSMa). A total of 152 obese patients prospectively underwent bariatric surgery and needle liver biopsy. Liver stiffness was measured by transient elastography 15 days before. To determine whether the LSM was overestimated, an expert operator retrospectively determined whether the skin-to-capsula distance was greater than 35 mm by analyzing the hyperechogenicity of ultrasound signals and the measured slope between 35 and 75 mm. In the case of an overestimation, a deeper measurement depth was selected to calculate the LSMa. There was an overestimation of the LSM obtained between 35 and 75 mm in 76 patients (50%). Among these patients, the LSMa was obtained between 40 and 75 mm in 49 patients and between 45 and 80 mm in 27 patients. Only the percentage of steatosis was independently and positively correlated with LSM overestimation. The areas under receiver operating characteristic of LSMa was 0.82±0.04 for predicting fibrosis stage F3. The Obuchowski measure was 0.85±0.02. The LSM was overestimated in severely obese patients obtained between 35 and 75 mm using an XL probe in 76 patients (50%), but LSM can be performed correctly in these patients after adapting the measurement depth to deeper beneath the patients' skin.

Treatment of Chronic Hepatitis C in the Aged - Does It Impact Life Expectancy? A Decision Analysis.

Background and AimsRecent studies have demonstrated that the efficacy of interferon-free direct-acting antiviral agents (DAAs) in patients over 70 is similar to that of younger age groups. Evidence continues to mount that life expectancy (LE) increases with successful treatment of hepatitis C (HCV) patients with advanced fibrosis. The evidence in older people is more limited. Our aim was to estimate the life year (LY) and quality-adjusted life year (QALY) gained by treatment of naïve patients with HCV as a function of patient's age and fibrosis stage.MethodsWe constructed a Markov model of HCV progression toward advanced liver disease. The primary outcome was LY and QALY saved. The model and the sustained virological response of HCV infected subjects treated with a fixed-dose combination of the NS5B polymerase inhibitor Sofosbuvir and the NS5A replication complex inhibitor Ledipasvir were based on the published literature and expert opinion.ResultsGenerally, both the number of LY gained and QALY gained gradually decreased with advancing age but the rate of decline was slower with more advanced fibrosis stage. For patients with fibrosis stage F1, F2 and F3, LY gained dropped below six months if treated by the age of 55, 65 or 70 years, respectively, while for a patient with fibrosis stage F4, the gain was one LY if treated by the age of 75. The QALY gained for treated over untreated elderly were reasonably high even for those treated at early fibrosis stage.ConclusionsThere is a significant life expectancy benefit to HCV treatment in patients up to age 75 with advanced-stage fibrosis.

Evaluation of the biomarker candidate MFAP4 for non-invasive assessment of hepatic fibrosis in hepatitis C patients.

BackgroundThe human microfibrillar-associated protein 4 (MFAP4) is located to extracellular matrix fibers and plays a role in disease-related tissue remodeling. Previously, we identified MFAP4 as a serum biomarker candidate for hepatic fibrosis and cirrhosis in hepatitis C patients. The aim of the present study was to elucidate the potential of MFAP4 as biomarker for hepatic fibrosis with a focus on the differentiation of no to moderate (F0–F2) and severe fibrosis stages and cirrhosis (F3 and F4, Desmet-Scheuer scoring system).MethodsMFAP4 levels were measured using an AlphaLISA immunoassay in a retrospective study including n = 542 hepatitis C patients. We applied a univariate logistic regression model based on MFAP4 serum levels and furthermore derived a multivariate model including also age and gender. Youden-optimal cutoffs for binary classification were determined for both models without restrictions and considering a lower limit of 80 % sensitivity (correct classification of F3 and F4), respectively. To assess the generalization error, leave-one-out cross validation (LOOCV) was performed.ResultsMFAP4 levels were shown to differ between no to moderate fibrosis stages F0–F2 and severe stages (F3 and F4) with high statistical significance (t test on log scale, p value <2.2·10−16). In the LOOCV, the univariate classification resulted in 85.8 % sensitivity and 54.9 % specificity while the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity (restricted approaches).ConclusionsWe confirmed the applicability of MFAP4 as a novel serum biomarker for assessment of hepatic fibrosis and identification of high-risk patients with severe fibrosis stages in hepatitis C. The combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0952-3) contains supplementary material, which is available to authorized users.