METAVIR Score Research Articles

Staging of Liver Fibrosis by Means of Semiautomatic Measurement of Liver Surface Nodularity in MRI

OBJECTIVE. The purposes of this study were to evaluate the accuracy of a semiautomatic method of measuring liver surface nodularity (LSN) on contrast-enhanced MR images and to compare the LSN score with pathologic fibrosis stage. MATERIALS AND METHODS. This retrospective study included patients who had undergone gadoxetate disodium-enhanced liver MRI 6 months before or after histopathologic investigation including percutaneous parenchymal biopsy and surgical biopsy for staging of chronic liver disease between January 2010 and December 2018. Semiautomated LSN quantification software was developed to measure LSN at MRI. Aspartate aminotransferase to platelet ratio index and fibrosis-4 index were derived from serum laboratory test results. The reference standard for staging of liver fibrosis was Metavir score. The accuracy of LSN score for staging of liver fibrosis was evaluated with AUC, and the optimal cutoff value was calculated by Youden index. Spearman correlation coefficient was used for correlation analysis. RESULTS. The study included 132 patients (93 men, 39 women). LSN score was evaluated without technical failure. There was high correlation between LSN score and Metavir score (Spearman ρ = 0.713, p < 0.001). The AUCs of LSN score for distinguishing Metavir score were 0.93 for F0-F1 versus F2-F4 (95% CI, 0.88-0.97; p < 0.001), 0.98 for F0-F2 vs F3-F4 (95% CI, 0.95-1.00; p < 0.001), and 0.83 for F0-F3 versus F4 (95% CI, 0.76-0.90; p < 0.001). The optimal cutoff value for differentiating F0-F2 from F3-F4 was 0.850 with 100% sensitivity and 85.4% specificity. CONCLUSION. LSN score calculated semiautomatically from MR images of the liver has high accuracy and correlates directly with the pathologic fibrosis stage.

Two-dimensional ultrasound shear wave elastography for identifying and staging liver fibrosis in pediatric patients with known or suspected liver disease: a clinical effectiveness study.

Ultrasound shear wave elastography (SWE) measures liver stiffness noninvasively, but few studies have defined cutoff values for detecting liver fibrosis in pediatric patients using 2-D ultrasound SWE. To evaluate the diagnostic performance of 2-D ultrasound SWE and define cutoff values for liver fibrosis in pediatric patients, using Canon (Toshiba) Aplio ultrasound systems. This was an institutional review board-approved retrospective study of patients (≤18years old) who had undergone both liver 2-D ultrasound SWE and percutaneous liver biopsy within 6months. Liver biopsies were staged using the METAVIR (fibrosis) scoring system. Continuous data were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic performance. Forty-six patients, with a median age of 11.5years (interquartile range: 8.0-14.3years), were included. Twenty-three patients were male (50%). Twenty-seven patients had a METAVIR fibrosis score of F0-1, and 19 patients had a score of F2-4. For differentiating METAVIR F0-1 from F2--4, the area under the ROC (AuROC) was 0.75 (95% confidence interval [CI]: 0.60-0.90). A cutoff of >1.89m/s yielded sensitivity of 73.7% (95% CI: 51.2-88.2) and specificity of 77.8% (95% CI: 59.2-89.4). For the subset of patients without histological hepatic steatosis (n=35), the AuROC was 0.86 (95% CI: 0.71-1.0). The same cutoff of >1.89m/s yielded a sensitivity of 80.0% (95% CI: 54.8-93.0) and specificity of 95.0% (95% CI 76.4-99.7). Two-dimensional ultrasound SWE distinguishes patients with no/mild fibrosis from those with moderate/severe fibrosis with good sensitivity and specificity. Diagnostic performance is comparable to that published for magnetic resonance elastography and is likely adversely impacted by steatosis.

Liver histology in children with glycogen storage disorders type VI and IX

BackgroundGlycogen storage diseases (GSD) type VI and IX are caused by liver phosphorylase system deficiencies and the two types are clinically indistinguishable. AimAs the role of liver biopsy is increasingly questioned, we aim to assess its current value in clinical practice. MethodsWe retrospectively reviewed children with diagnosis of GSD VI and IX at a paediatric liver centre between 2001 and 2018. Clinical features, molecular analysis and imaging were reviewed. Liver histology was reassessed by a single histopatologist. ResultsTwenty-two cases were identified (9 type VI, 9 IXa, 1 IXb and 3 IXc). Features at presentation were hepatomegaly (95%), deranged AST (81%), short stature (50%) and failure to thrive (4%). Liver biopsy was performed in 19 patients. Fibrosis varied in GSD IXa with METAVIR score between F1-F3 and ISHAK score of F2-F5. METAVIR score was F2-F3 in GSD VI and F3-F4 in GSD IXc. Hepatocyte glycogenation, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining were also demonstrated. ConclusionsAlthough GSD VI and IX are considered clinically mild, chronic histological changes of varying severity could be seen in all liver biopsies. Histopathological assessment of the liver involvement is superior to biochemical parameters, but definitive classification requires a mutational analysis.

Virtual Touch Quantification using Acoustic Radiation Force Impulse Imaging Technology versus Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Patients with Chronic Hepatitis B or C using Liver Biopsy as the Gold Standard.

Our aim was to assess the diagnostic performance of transient elastography (TE) and Virtual Touch Quantification (VTQ), a point Shear Wave Elastography (pSWE) technique, using Acoustic Radiation Force Impulse (ARFI) technology, for liver fibrosis assessment, as compared to percutaneous liver biopsy (LB), in patients with chronic hepatitis B or C. We analyzed 157 patients (80 with chronic hepatitis B and 77 with chronic hepatitis C) with reliable liver stiffness (LS) measurements, in whom we compared TE and VTQ to the LB performed during the same session (evaluated according to the Metavir scoring system: F0-F4). LS was assessed by TE (FibroScan, EchoSens, Paris, France) and VTQ using the Siemens Acuson S2000TM ultrasound system (Siemens AG, Erlangen, Germany). We defined reliable LS measurements as the median value of 10 measurements with an IQR/M <30% for both TE (obtained using the M probe) and VTQ. The areas under receiver operating characteristic curves (AUROCs) were used to assess the diagnostic performance of TE and VTQ. Correlation analysis determined the relationship between LSM values and liver histology. On LB 31 (19.7%) patients had no fibrosis, 35 (22.3%) had F1, 43 (27.4%) had F2, 28 (17.8%) had F3 and 20 (12.7%) had cirrhosis. The mean size of the liver specimen in LB was 27 mm. A strong, linear correlation (Spearman ρ=0.826; p<0.001) with 95% confidence interval for rho (0.769- 0.870), was found between the TE and VTQ measurements. By comparing the AUROC curves, TE and VTQ had similar predictive values for the presence of F≥1 Metavir: AUROC TE=0.876, AUROC VTQ=0.832, p=0.358, for F≥2 Metavir: AUROC TE=0.826, AUROC VTQ=0.862, p=0.313, for F≥3 Metavir: AUROC TE=0.907, AUROC VTQ=0.880, p=0.434 and for F=4 Metavir: AUROC TE=0.981, AUROC VTQ=0.974, p= 0.423. Both methods, TE and VTQ (pSWE) offer excellent diagnostic accuracy for liver fibrosis assessment in patients with chronic hepatitis B or C with similar performance.

405-P: Relationship between NAFLD and Cardiac Complications and Function in T2DM

NAFLD is common in T2DM patients and has been proposed to be part of the cardiometabolic syndrome. Aim: To determine the relationship between hepatic fibrosis and cardiovascular abnormalities in T2DM. Subjects: 72 T2DM patients with NAFLD and 38 T2DM without NAFLD were studied. Based upon liver elastography and Bonacini and Metavir scores T2DM patients with NAFLD were divided into 3 groups: (I) NAFLD with hepatic fibrosis ≥F2 (n=29); (II) NAFL without fibrosis/inflammation (n=11); (III) NASH (n=32). All subjects had cardiac echo to quantitate ventricular volumes, ejection fraction, and diastolic function. Results: Incidence of cardiovascular complications was higher in patients with hepatic fibrosis: prevalence of arterial hypertension was 40% in T2DM without NAFLD vs. 44 % in NAFL, 69 % in NASH (p&amp;lt;0.01) and 70 % in hepatic fibrosis (p&amp;lt;0.001). Coronary heart disease was present in 20% of T2DM patients without NAFLD, 37% with NAFL, 36 % with NASH and 53 % with hepatic fibrosis (p&amp;lt;0.001). No patient with T2DM without NAFLD had non-fatal myocardial infarction; MI was present in 3.7% of patients with NAFL, 1.7 % with NASH and 15 % with hepatic fibrosis. 3.2% of patients with hepatic fibrosis had stroke; no other patient had stroke. Ejection fraction was decreased (p&amp;lt;0.05) in patients with NASH (57 ±3%) and hepatic fibrosis (54 ±2%) vs. NAFL patients (66 ±2%) and T2DM without NAFLD (63 ±1%). End-diastolic volume was increased in patients with NAFL (189 ±6 ml) and NASH (125±8 ml) vs. hepatic fibrosis (106±3ml) and T2DM patients without NAFLD (110±6 ml). End-systolic volume was increased in patients with NAFL (58±5 ml), NASH (55±3 ml) and hepatic fibrosis (48±4 ml) vs. T2DM without NAFLD (42±4 ml). Conclusion: Liver fibrosis in T2DM is associated with impaired cardiac function and increased cardiovascular complications. The results demonstrate that hepatic inflammation and fibrosis in T2DM patients with NAFLD is an important risk factor for cardiovascular disease and is associated with cardiac dysfunction. Disclosure O. Lavrynenko: None. O. Zemlianitsyna: None. I. Dunaeva: None. N. Kravchun: None. V. Sinaiko: None. R.A. DeFronzo: None.

The Enhanced Liver Fibrosis Index Predicts Hepatic Fibrosis Superior to FIB4 and APRI in HIV/HCV Infected Patients.

Accurate noninvasive biomarkers of fibrotic progression are important for hepatitis C virus (HCV) management, but commonly used modalities may have decreased efficacy in human immunodeficiency virus (HIV)/HCV-coinfected persons. The enhanced liver fibrosis (ELF) index is a highly sensitive noninvasive marker of hepatic fibrosis that has had limited assessment in the HIV/HCV population. We compared ELF index performance to FIB4 and aspartate to platelet ratio index (APRI) at different stages of liver fibrosis as determined by liver histology, and validated the efficacy of the three noninvasive biomarkers in HIV/HCV-coinfected versus HCV-monoinfected. The ELF index was determined in 147 HIV/HCV-coinfected and 98 HCV-monoinfected persons using commercial ELISA assays for the component elements of the index. Area under the receiver-operator curve was used to validate ELF and to compare its performance to liver histology as well as to other noninvasive biomarkers of liver fibrosis, FIB4, and APRI. The ELF index increased with histological stage of liver fibrosis and exhibited a linear relationship with Metavir score in all subjects. ELF performance was comparable between HIV/HCV and HCV with advanced liver fibrosis/cirrhosis. In the HIV/HCV cohort ELF cutoffs of 8.45 and 9.23 predicted mild and moderate fibrosis with 85% sensitivity, whereas the ELF cutoff of 9.8 had the highest specificity for advanced fibrosis and the cutoff of 10.4 was 99% specific for cirrhosis. ELF performance was superior to FIB4 and APRI in all subjects regardless of HIV status. ELF index demonstrated excellent characteristics toward accurate prediction of liver fibrosis and cirrhosis with superior performance to APRI and FIB4 in HIV/HCV coinfection. Applying this noninvasive biomarker index for diagnosis of liver fibrosis and progression in HIV/HCV is warranted.

Comparison of serum fibrosis biomarkers for diagnosing significant liver fibrosis in patients with chronic hepatitis B.

Chronic hepatitis B (CHB) virus continues to be a leading cause of morbidity and mortality worldwide. The diagnosis of liver fibrosis has a key role in selecting patients with CHB for antiviral treatment. However, serum biomarkers demonstrate limited diagnostic utility. The present study aimed to compare the performances of fibrosis biomarkers for diagnosing significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB and to identify the most appropriate biomarker for these patients. The current study included 96 antiviral-naïve patients with CHB who underwent liver biopsy. METAVIR scoring system was used to assess liver fibrosis and necroinflammation. The diagnostic performances were evaluated of the platelet (PLT) count; the levels of hyaluronan, serum 7S domain of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer (M2BPGi) and N-terminal type III collagen propeptide (Pro-C3); the fibrosis index based on four factors; the aspartate aminotransferase-to-platelet ratio index; and enhanced liver fibrosis score for identifying significant liver fibrosis [≥fibrosis stage 2 (F2)]. All fibrosis biomarkers, except the Pro-C3 level, correlated with the fibrosis stage. M2BPGi was better than other biomarkers for diagnosing ≥F2, with the highest area under the curve of 0.902. M2BPGi demonstrated a higher diagnostic accuracy for significant fibrosis than mild/severe fibrosis or cirrhosis. However, no significant correlation was observed between the M2BPGi level and fibrosis stage in patients with CHB having significant liver necroinflammation defined as ≥ necroinflammatory activity 2. The M2BPGi level and PLT count were exclusively correlated with the fibrosis stage in 73 patients without significant liver necroinflammation. M2BPGi demonstrated the highest diagnostic performance for significant fibrosis in patients having significant liver fibrosis with no significant liver necroinflammation. In conclusion, the M2BPGi level can accurately diagnose significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB.

Subclinical liver fibrosis in patients with idiopathic pulmonary fibrosis.

Data on the presence of subclinical fibrosis across multiple organs in patients with idiopathic lung fibrosis (IPF) are lacking. Our study aimed at investigating through hepatic transient elastography (HTE) the prevalence and clinical impact of subclinical liver fibrosis in a cohort of patients with IPF. Patients referred to the Centre for Rare Lung Disease of the University Hospital of Modena (Italy) from March 2012 to February 2013 with established diagnosis of IPF and without a documented history of liver diseases were consecutively enrolled and underwent HTE. Based on hepatic stiffness status as assessed through METAVIR score patients were categorized as "with liver fibrosis" (corresponding to a METAVIR score of F1-F4) and "without liver fibrosis" (METAVIR F0). Potential predictors of liver fibrosis were investigated through logistic regression model among clinical and serological variables. The overall survival (OS) was assessed according to liver fibrosis and multivariate Cox regression analysis was used to identify independent predictors. In 13 out of 37 patients (35%) with IPF, a certain degree of liver fibrosis was documented. No correlation was found between liver stiffness and clinical-functional parameters. OS was lower in patients 'with liver fibrosis' than in patients 'without liver fibrosis' (median months 33 [23-55] vs. 63 [26-94], p = 0.038). Patients 'with liver fibrosis' presented a higher risk of death at seven years as compared to patients 'without liver fibrosis' (HR = 2.6, 95% CI [1.003-6.7], p = 0.049). Higher level of AST to platelet ratio index (APRI) was an independent predictor of survival (HR = 4.52 95% CI [1.3-15.6], p = 0.02). In our cohort, more than one-third of IPF patients had concomitant subclinical liver fibrosis that negatively affected OS. These preliminary claims further investigation aimed at clarifying the mechanisms beyond multiorgan fibrosis and its clinical implication in patients with IPF.

Shear Wave Elastography Performance in Noninvasive Assessment of Liver Cirrhosis in Liver Transplant Recipients With the Recurrence of Hepatitis C Infection

BackgroundThe recurrence of hepatitis C (HCV) after liver transplant (LTX) leads to graft fibrosis and cirrhosis. Liver biopsy remains the criterion standard for their diagnosis and monitoring. Our objective was evaluation of shear wave elastography (SWE) in patients with HCV recurrence after LTX and its comparison with histopathologic fibrosis assessment scoring systems. MethodsA total of 101 LTX recipients with HCV recurrence (42 women [41.6%] and 59 men [58.4%]) were evaluated by graft biopsy specimens (Ishak, Scheurer, and meta-analysis of histologic data in viral hepatitis [Metavir] score) and SWE (liver stiffness). Median age of patients was 59.4 years; median time from LTX was 84.9 months. The study protocol conforms with the Declaration of Helsinki. ResultsMedian liver stiffness was 21.3 kPa. To differentiate between liver fibrosis and cirrhosis, patients were divided into 2 subgroups: Ishak score fibrosis (1-4 [85.2%]) and cirrhosis (5-6 [13.9%]); Scheurer score fibrosis (0-3 [85.2%]) and cirrhosis (4 [12.9%]); Metavir score fibrosis (0-3 [85.2%]) and cirrhosis (4 [14.9%]). We have observed statistically significant differences between liver fibrosis and liver cirrhosis groups defined on the basis of Ishak, Scheurer, and Metavir scoring systems: 20.8 kPa vs 29.6 kPa (P = .001), 20.7 kPa vs 30.3 kPa (P = .0005), and 20.7 kPa vs 28.8 kPa (P = .002), respectively. ConclusionsOur results indicate that SWE may be useful in differentiating patients with advanced cirrhosis from those with fibrosis and may be helpful in the noninvasive diagnosis and monitoring of HCV recurrence after LTX.

Platelet count is closely associated with the severity of liver injury in patients with chronic hepatitis B virus infection: A cross-sectional study.

Although the platelet count may provide clues regarding the severity of liver disease, there are currently no available data supporting the utility of the platelet count to evaluate the degree of liver injury in patients with chronic hepatitis B virus (HBV) infection. The present study aimed to determine the association between the platelet count and the severity of liver injury in patients with chronic HBV infection. A total of 941 patients were included and were stratified into a Child-Turcotte-Pugh (CTP) class A group and a CTP class B/C group using the CTP scoring system. A total of 53 patients underwent liver biopsy. The pathological stage F4 was defined as cirrhosis based on the METAVIR scoring system. Compared with that in patients with CTP class A, the platelet count in patients with CTP class B/C was lower (P<0.001). Similarly, for patients with normal alanine aminotransferase (ALT) levels, the platelet count was significantly different between the CTP class B/C and A groups (P<0.001). The platelet count was inversely correlated with the CTP score (r=-0.420, P<0.001) and independently associated with CTP grade B/C [odds ratio (OR), 0.994; 95% CI, 0.990-0.999; P=0.009]. The area under the receiver operating characteristic curve (AUC) of the platelet count to distinguish CTP grade B/C from A was 0.712 and 0.791, respectively, in all patients with HBV infection and the subset with normal ALT levels. In addition, compared to patients with chronic hepatitis B, patients with cirrhosis had a lower platelet count and higher aspartate transaminase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) (P<0.001). The platelet count was inversely correlated with FIB-4 (r=-0.855, P<0.001) and APRI (r=-0.741, P<0.001). The AUC for the platelet count to distinguish cirrhosis from chronic hepatitis B was 0.927 (sensitivity, 78.76%; specificity, 92.22%). Among patients who underwent liver biopsy, the platelet count in those with F4 was lower compared with that in patients with ≤F3 (P=0.013). The platelet count was inversely correlated with the pathological stage (r=-0.295, P=0.032) and was independently associated with F4 (OR, 0.978; 95% CI, 0.960-0.997; P=0.026). The AUC of the platelet count to distinguish F4 from patients with ≤F3 was 0.761. In conclusion, the platelet count may be used as a non-invasive marker to assess the severity of liver injury and of liver fibrosis in patients with chronic HBV infection.

Interface Hepatitis over Grade 2 May Differentiate Chronic Inflammation Associated with CHB from NAFLD in the Early Stage.

Background Patients with chronic hepatitis B (CHB) concomitant with nonalcoholic fatty liver disease (NAFLD) are increasing. Objectives To identify pathological features that can be used to differentiate between chronic inflammation caused by CHB and that caused by NAFLD. Methods Patients with CHB (n = 31) needing antiviral treatment, NAFLD (n = 50), or CHB-NAFLD (n = 51) who underwent biopsy were retrospectively enrolled. Pathological characteristics of chronic inflammation were evaluated using the METAVIR scoring system. The rates of three pathological characteristics were first compared in patients with NAFLD and those with CHB, then compared after fibrosis matching, and were finally compared in CHB-NAFLD patients with different viral loads. Results The rates of interface hepatitis over grade 2 and fibrosis over grade 2 were significantly higher in the CHB group than in the NAFLD group (100% vs. 4% and 80.6% vs. 22%; both P < 0.0001), while no significant difference was observed in the rate of lobular inflammation over grade 2 between the two groups. After fibrosis matching, in patients with F0–2 fibrosis, the rate of interface hepatitis over grade 2 in CHB was significantly higher than that in NAFLD (100% vs. 0%; P < 0.0001). In CHB-NAFLD patients with F0–2 fibrosis, the rate of interface hepatitis over grade 2 in cases with a high viral load was significantly higher than cases with a low viral load (66.6% vs. 0%; P < 0.0001). The rate of lobular inflammation showed no difference between groups. Conclusion Interface hepatitis over grade 2 can be used for the differential diagnosis of chronic inflammation associated with CHB or NAFLD in the early stage.

Causative factors of liver fibrosis in HIV-infected patients. A single center study

BackgroundLiver disease is a leading cause of morbidity and mortality among Human Immunodeficiency virus (HIV) infected patients; however no consensus exists on HIV-related risk factors for it. The aim of this study was to identify risk factors for liver fibrosis/cirrhosis in a cohort of Greek HIV-infected patients.MethodsPatients attending the HIV outpatient clinic of Pathophysiology Department at «Laiko» General Hospital in Athens, Greece, between December 2014 and December 2017 were eligible for inclusion. Inclusion criteria were confirmed HIV infection and age > 18 years. Exclusion criteria were Body-Mass index (BMI) > 40, liver metastases of malignant diseases and concurrent or previous chemotherapy.Liver stiffness (LS) was measured using Vibration Controlled Transient Elastography (TE) and laboratory tests were acquired in all patients. Patients were classified in 2 groups: those with mild or no fibrosis (equivalent to Metavir score F0-F2) and those with significant fibrosis (equivalent to Metavir score F3-F4).ResultsA total of 187 consecutive patients were included in this study. Median TE value was 5.1 kilopascals (KPa) (range 2.8–26.3), with 92.5% (173/187) of the patients having no/mild fibrosis and 7.4% (14/187) significant fibrosis.On multivariate logistic regression analysis older patient’s age, abnormal serum aspartate aminotransferase (AST) value, Hepatitis C virus (HCV) infection, alcohol abuse, CD4/CD8 ratio and an increased number of liver related events (LREs) were significantly correlated with liver fibrosis/cirrhosis.ConclusionsIn our cohort of HIV-infected individuals HCV/HIV co-infection, older age, alcohol abuse and CD4/CD8 ratio seem to correlate with fibrogenesis in the liver.

Histological Differences in Naiive Chronic Hepatitis B Patients with Normal and Elevated ALT

AbstractBackground and aims: HBV infection is a significant public health issue all over the world. Egypt shows marked variations of HBV prevalence by age, gender, and geographical distribution. Treatment guidelines for CHB are based on serum ALT, together with HBV viral load and liver inflammation or fibrosis. Our study aimed to compare histological findings between CHB patients with ALT levels >ULN and patients with normal levels.Methods: Twenty-nine CHB adult Egyptian patients were included in our cross-sectional study. Liver biopsy was performed for all patients to detect fibrosis stage and inflammation grade using the METAVIR score, which was used to divide patients into two groups: patients with mild to moderate fibrosis (F0-1-2) and patients with advanced fibrosis (F3-4). Patients were also categorized into patients with ALT normal ALT; and Patients with ALT values > ULN.Results: We found that moderate to severe inflammation was detected in 56.7% of cases with normal ALT compared to 28% of cases with raised ALT (P = 0.015). Advanced fibrosis was detected in 10.44% of cases with normal ALT and 20% of cases with raised ALT without a statistically significant difference between both groups.Conclusions: Liver injury is present in a considerable proportion of patients with normal and those with mild ALT rise, so, these cases need careful evaluation in order not to miss a treatment indication.

Diagnostic Value of Serum Procollagen III N-Terminal Peptide for Liver Fibrosis in Infantile Cholestasis.

Background: Several non-invasive markers have been reported as being effective for the assessment of fibrosis in adults with chronic viral hepatitis. The infantile liver is more susceptible to cholestasis, and it is important to promptly evaluate liver fibrosis to guide the clinical treatment. However, the clinical value of these markers in infants with cholestasis remains unknown.Aim: To investigate the correlation between serum laminin (LN), hyaluronic acid (HA), procollagen III N-terminal peptide (PIIINP) level, and liver fibrosis stage in infants with cholestasis.Methods: One hundred and thirty-seven term infants with cholestasis were included. Laparoscopic exploration and cholangiography were performed to diagnose or rule out biliary atresia. Serum LN, HA, and PIIINP were measured prior to laparoscopic exploration. Liver biopsy was performed for all patients. Liver fibrosis was staged on a five-point scale (F0–F4) according to the METAVIR scoring system. The correlation between serum markers and liver fibrosis stage was assessed. A receiver operator characteristic analysis was performed to determine the accuracy of serum markers for predicting the liver fibrosis stage.Results: Serum PIIINP and HA were positively correlated with liver fibrosis stage (r = 0.622, P < 0.001, and r = 0.41, P < 0.001, respectively). There was no significant correlation between serum LN and liver fibrosis stage (P > 0.05). Serum aspartate aminotransferase, total bilirubin, direct bilirubin, and PIIINP were independently correlated with the fibrosis stage on multivariate ordinal regression analysis. Receiver operating curve (ROC) analysis showed that serum PIIINP was the most effective for the diagnosis of fibrosis grade. The area under the ROC curves (AUROCs) for serum PIIINP for diagnosing fibrosis stages ≥F1, ≥F2, ≥F3, and F4 (cirrhosis) were 0.843, 0.789, 0.82, and 0.891, respectively. The cut-off serum PIIINP value for predicting fibrosis stage ≥F1 was 242.3 ng/mL, with 73.8% sensitivity and 90% specificity. The cut-off value for predicting cirrhosis was 698.7 ng/mL, with 75% sensitivity and 96% specificity.Conclusion: Serum PIIINP is a promising biomarker for predicting liver fibrosis stage, especially cirrhosis. Its assessment is a simple and non-invasive diagnostic method for liver fibrosis in infants with cholestasis.

Correlation of hepatic fibrosis assessed by Metavir score and digital morphometry in a murine model

Animal models for hepatic fibrosis are currently used for clinical studies, and research works aimed to the progression and regression of the disease. In these, fibrosis is evaluated using histopathological assessment with high variability inter- and intra-observers. Digital morphometry in the space color LAB could reduce this variability; however, its correlation degree with the histopathological assessment is unknown. Objective: The objective of the study was to analyze the correlation between digital morphometry and the histopathological assessment of hepatic fibrosis in images of biopsies of a murine model. Materials and methods: We performed a descriptive, experimental, longitudinal, prospective, analytical, and correlational study. Fibrosis was induced by intraperitoneal injection of carbon tetrachloride in 16 Wistar male rats. We did a postmortem hepatectomy and took histological specimens stained by Masson trichrome, obtaining ten randomly selected images at ×10 in each liver. We quantified the fibrosis percentage (FP) by digital morphometry and compared it to the Metavir score given by three independent evaluators. FP was analyzed by a ANOVA test and Spearman Rho test. Results: The evaluated images had 70% concordance of the three evaluators. The analysis of the FP revealed fibrosis evaluation groups with statistical differences. The FP had a very high correlation with the histopathological diagnosis (p = 0.0001, r = 0-9). The ranges obtained from FP for each phase of fibrosis were: 0.4% for F0, 0.44-1.14% for F1, 1.52-2.74% for F2, 3.1-3.8% for F3y, and 5.12-6.12% for F4. Conclusions: The morphometric quantification had a high correlation with the histopathological evaluation of images of histological sections of liver biopsies of the murine model of fibrosis. The quantification of the FP by digital morphometry will be useful to increase the accuracy in the evaluation of liver fibrosis

Moringa oleifera Inhibits Liver Fibrosis Progression by Inhibition of α-Smooth Muscle Actin, Tissue Inhibitors of Metalloproteinases-1, and Collagen-1 in Rat Model Liver Fibrosis

OBJECTIVE: This research was conducted to prove the existence of an anti-fibrosis effect in the ethanol extract of Moringa oleifera (MO) leaves on the liver.&#x0D; MATERIALS AND METHODS: The liver fibrosis rat model was injected with chronic CCl4. The ethanol extract of MO leaves was divided into three doses (150, 300, and 600 mg/kg body weight) and given through oral gavage.&#x0D; RESULTS: The results of the histopathological analysis showed that the administration of MO ethanol extract could inhibit liver fibrosis as indicated by lower METAVIR scores than positive control rats. The immunohistochemical expression of collagen-1 in MO-fed rats also showed a decrease. The same thing was seen in the double-immunofluorescence staining analysis of α-SMA and tissue inhibitors of metalloproteinases-1 (TIMP-1), where the administration of MO ethanol extract decreased both markers.&#x0D; CONCLUSIONS: This study concluded that the increase in collagen-1, α-SMA, and TIMP-1 simultaneously caused a more severe degree of fibrosis (METAVIR score). The ethanol extract of MO leaves was proven to be able to inhibit the progression of liver fibrosis by reducing the expression of all three markers.

Blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue injury in chronic hepatitis C patients.

Oxidative stress is the process by which reactive molecules and free radicals are formed in cells. In this study, we report the blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue inchronic hepatitis C (CHC) patients by using real-time PCR. A total of 144 untreated patients diagnosed with CHC having genotype 3a and 20 healthy controls were selected for the present study. Liver biopsy staging and grading of CHC patients were performed using the METAVIR score. Total RNA was extracted from liver tissue and blood samples, followed by cDNA synthesis and real-time PCR. The relative expression of genes was calculated using the ΔΔCt method. The expression profile of 84 genes associated with oxidative stress and antioxidants was determined in liver tissue and blood samples. In liver tissue, 46 differentially expressed genes (upregulated, 27; downregulated, 19) were identified in CHC patients compared to normal samples. In blood, 61 genes (upregulated, 51; downregulated; 10) were significantly expressed in CHC patients. A comparison of gene expression in liver and whole blood showed that 20 genes were expressed in a similar manner in the liver and blood. The expression levels of commonly expressed liver and blood-based genes were also correlated with clinical factors in CHC patients. A receiver operating curve (ROC) analysis of oxidative stress genes (ALB, CAT, DHCR24, GPX7, PRDX5, and MBL2) showed that infections in patients with CHC can be distinguished from healthy controls. In conclusion, blood-based gene expression can reflect the behavior of oxidative stress genes in liver tissue, and this blood-based gene expression study in CHC patients explores new blood-based non-invasive biomarkers that represent liver damage.

Baseline Amino Acid Substitutions in the NS5A ISDR and PKR Binding Domain of Hepatitis C and Different Fibrosis Levels and Levels of Development of Hepatocellular Carcinoma in Patients Treated with DAAs.

Variations in the interferon sensitivity-determining region (ISDR) within the NS5A region were related to the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). The aim of the study was to investigate a relationship between ISDR/PKR substitutions and their association with liver fibrosis or HCC development. A total of 316 patients infected with HCV and treated with DAAs were evaluated. HCV RNA was quantified and sequenced before treatment. The liver fibrosis stage was assessed by transient elastography and equalized to METAVIR scores. Multivariate analysis showed that ≥3 substitutions in ISDR and ≥6 in PKR-bd were significantly associated with advanced fibrosis. Advanced fibrosis was observed in patients with higher substitutions in ISDR and PKR-bd. A higher correlation between advanced fibrosis and a high frequency of ≥3 substitutions in ISDR and ≥6 in PKR-bd was observed in patients infected with genotype 2c. In addition, in a higher proportion of HCC patients, advanced fibrosis (40.4% vs. 88.2%; p < 0.001) and ≥6 substitutions in PKR-bd (15.4% vs. 41.2%; p = 0.01) was observed. In conclusion, a higher number of substitutions in ISDR and PKR-bd were associated with advanced liver fibrosis, suggesting a use of like predictors for progression in the liver damage. A significantly higher number of PKR-bd substitutions was observed in HCC patients; in particular, in patients infected with HCV genotype 2c.

Corrected integrated density: a novel method for liver elastic fibers quantification in chronic hepatitis C

BackgroundElastic fibers deposition is triggered during liver fibrosis and is related to worse clinical prognosis in chronic hepatitis C patients. This study aimed to verify if a new method for elastic fiber quantification can be used to discriminate between different degrees of fibrosis in liver biopsies of patients with hepatitis C.MethodsIndividuals presenting with different degrees of fibrosis in liver biopsy were included. Slides of liver samples were stained with orcein with and without prior oxidation. Morphometric analysis was proceeded, and quantification accomplished by corrected integrated density.ResultsTwenty-seven patients, mean age 52 years-old, 59% women, were included. Elastic fibers density was higher in advanced fibrosis patients and there was a positive correlation with Metavir score (Spearman r = 0.609, p < 0.001), as well as with the noninvasive scores Fib-4 (Pearson r = 0.46, p = 0.029) and APRI (r = 0.52, p = 0.01).ConclusionMorphometric analysis by corrected integrated density demonstrates that elastic fibers abundance is higher in advanced stage of fibrosis in patients with hepatitis C.

Performance of B-mode ratio and 2D shear wave elastography for the detection and quantification of hepatic steatosis and fibrosis after liver transplantation.

To evaluate the diagnostic performance of B-mode ratio and shear wave elastography (SWE) for the assessment of steatosis and liver fibrosis after liver transplantation. Patients hospitalized for a systematic check-up after liver transplantation underwent the same day hepatic ultrasound with B-mode ratio and SWE, followed by liver biopsy and biological examinations. Steatosis was measured using hepatorenal sonographic index of B-mode ratio and liver stiffness using SWE. Liver biopsy, used as gold standard, graded steatosis S0(<5%), S1(5-<33%), S2(33-<66%), or S3(≥66%) and liver fibrosis according to the Metavir score. The results were tested against two external validation cohorts. Fifty-eight patients were included. Mean B-ratio value was significantly higher in patients with steatosis (0.95 ± 0.13 versus 1.39 ± 0.41, P < 0.001). A B-mode ratio cutoff values at least 0.985 was found optimal for steatosis' detection [area under the receiver operating characteristic curve (AUROC) 0.902 ± 0.05, sensitivity 95%, specificity 79%]. A B-mode ratio value below 0.9 ruled out steatosis and above 1.12 ruled in steatosis. Mean SWE value for patients without significant fibrosis (≤F1) was 15.90 ± 9.2 versus 19.27 ± 7.7 kPa for patients with fibrosis (P = 0.185). A 2D-SWE value below 7.85 kPa ruled out significant fibrosis and above 26.35 kPa ruled it in. The B-mode ratio is an efficient and accurate tool for the noninvasive diagnostic of steatosis in postliver transplantation patients. Yet, because liver stiffness is higher in postliver transplantation patients, 2D-SWE is not reliable in the diagnosis of significant fibrosis after liver transplantation.