Necroinflammatory Activity Grade Research Articles

Prediction of Early-stage Liver Fibrosis Using FDG-PET/CT.

18F-fluorodeoxyglucose (FDG) is known to accumulate in the liver. We investigated whether accumulation of FDG was correlated with the degree of liver fibrosis and the grade of necro-inflammatory activity. This retrospective study included 35 patients who underwent FDG-positron emission tomography (PET)/computed tomography (CT) before liver surgery. On fusion images of CT and PET, by placing regions of interest on the lateral, anterior and posterior segments of the liver and the aorta, the standardized uptake value (SUV) mean, and SUV normalized by lean body mass (SUL) mean of the liver were measured, and the ratio SUVmean liver/SUVmean aorta was calculated. According to the New Inuyama Classification, subjects were classified into three groups based on the grade of liver-fibrosis degree, i.e., F0, F1+F2 and F3+F4, and into three groups based on the grade of necro-inflammatory activity, i.e., A0, A1 and A2. Each of the above parameters was then compared among the groups using a Tukey test. Average SULmean liver values of the F0, F1+F2 and F3+F4 groups were 1.573±0.211, 1.845±0.220 and 1.716±0.119, respectively. The SULmean liver of the F1+F2 group was significantly higher than that of the F0 group (p=0.0296). No significant difference was observed for the other two parameters. None of the parameters exhibited significant difference among the A0, A1, and A2 groups. FDG accumulation in the liver may be increased in the early stage of liver fibrosis. SULmean liver could be used to determine the necessity for therapeutic intervention in chronic liver disease.

Gd-EOB-DTPA-enhanced MRI-a noninvasive and short-term assessment method for liver necroinflammation after direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C.

To assess liver necroinflammation in HCV patients undergone antiviral therapy by Gd-EOB-DTPA-enhanced MRI with histopathologic analyses as reference. HCV patients were enrolled in this prospective study before antiviral treatment between 09-2016 and 07-2017. Unenhanced MR, Gd-EOB-DTPA-enhanced MR, and liver biopsy were performed before and 24 weeks after treatment of daclatasvir with asunaprevir (DAA). DWI was obtained using a breath-hold single-shot echo planar spin-echo sequence. Twenty minutes after administration of Gd-EOB-DTPA, the relative enhancement (RE) and the contrast enhancement index (CEI) were recorded. Liver necroinflammatory activity grades (G0-18) were categorized on the Ishak Scoring systems. CEI, RE, and DWI of baseline and 24 weeks after treatment were compared by paired t test. Relationship between MR parameters and histologic scores was evaluated by Pearson's correlation. Receiver operating characteristic analysis evaluated the measurements' diagnostic performance. MRI variability between two readers was assessed using the intraclass correlation coefficient.Results RESULTS: A decrease of liver necroinflammatory activity grade (p < 0.0001) was detected in final cohort (n = 21; mean age 44years; 23 to 67years; 11 F, 10M). Statistical results of 42 person-times in 21 patients at baseline and follow-up showed CEI and ADC were significantly different (p = 0.006 and 0.036) across histologic grades of liver necroinflammation. Significant increase of CEI, RE, and ADC (p = 0.0004, 0.0032, 0.0110) 24 weeks after DAA treatment was seen. Additionally, CEI was correlated to necroinflammatory grade (r = - 0.596, p = 0.006). AUROC for CEI, ADC, and CEI combined with ADC to differentiate patients with none and mild (G0-6) from patients with moderate and severe necroinflammation (G7-18) was 0.834 (95% CI 0.712-0.956, 0.724(95% CI 0.565-0.884) and 0.837(95% CI 0.717-0.956). Gd-EOB-DTPA-enhanced MRI by CEI could be used as a noninvasive imaging biomarker to distinguish grades of necroinflammatory activity in patients with HCV after DAAs therapy at early stage and CEI combined with ADC could get a better diagnostic accuracy.

Necro-inflammatory activity grading in chronic viral hepatitis with three-dimensional multifrequency MR elastography

The purpose of this study was to assess the diagnostic value of multifrequency MR elastography for grading necro-inflammation in the liver. Fifty participants with chronic hepatitis B or C were recruited for this institutional review board-approved study. Their liver was examined with multifrequency MR elastography. The storage, shear and loss moduli, and the damping ratio were measured at 56 Hz. The multifrequency wave dispersion coefficient of the shear modulus was calculated. The measurements were compared to reference markers of necro-inflammation and fibrosis with Spearman correlations and multiple regression analysis. Diagnostic accuracy was assessed. At multiple regression analysis, necro-inflammation was the only determinant of the multifrequency dispersion coefficient, whereas fibrosis was the only determinant of the storage, loss and shear moduli. The multifrequency dispersion coefficient had the largest AUC for necro-inflammatory activity A ≥ 2 [0.84 (0.71–0.93) vs. storage modulus AUC: 0.65 (0.50–0.79), p = 0.03], whereas the storage modulus had the largest AUC for fibrosis F ≥ 2 [AUC (95% confidence intervals) 0.91 (0.79–0.98)] and cirrhosis F4 [0.97 (0.88–1.00)]. The measurement of the multifrequency dispersion coefficient at three-dimensional MR elastography has the potential to grade liver necro-inflammation in patients with chronic vial hepatitis.

Magnetic resonance quantitative susceptibility mapping in the evaluation of hepatic fibrosis in chronic liver disease: a feasibility study.

Noninvasive methods for the early diagnosis and staging of hepatic fibrosis are needed. The present study aimed to investigate the alteration of magnetic susceptibility in the liver of patients with various fibrosis stages and to evaluate the feasibility of using susceptibility to stage hepatic fibrosis. A total of 30 consecutive patients with chronic liver diseases (CLDs) underwent magnetic resonance imaging (MRI) and liver biopsy evaluation of hepatic fibrosis, necroinflammatory activity, iron load, and steatosis. Quantitative susceptibility mapping (QSM), R2* and proton density fat fraction (PDFF) images were postprocessed from the same gradient-echo data for quantitative tissue characterization using region of interest (ROI) analysis. The differences for MRI measurements between cohorts of non-significant (Ishak-F <3) and significant fibrosis (Ishak-F ≥3) and the correlation of MRI measurements with fibrosis stages and necroinflammatory activity grades were tested. Receiver operating characteristic (ROC) analysis was also performed. There was a significant difference in liver susceptibility between the cohorts of significant and non-significant fibrosis (Z=-2.880, P=0.004). A moderate negative correlation between the stages of liver fibrosis and liver susceptibility was observed (r=-0.471, P=0.015). Liver magnetic susceptibility differentiated non-significant from significant hepatic fibrosis with an area under the receiver operating curve (AUC) of 0.836 (P=0.004). A highly sensitive diagnostic performance with an AUC of 0.933 was obtained using magnetic susceptibility and PDFF together (P<0.001). A noninvasive liver QSM-based evaluation promises an accurate assessment of significant fibrosis in patients with CLDs.

A noninvasive model to predict liver histology for antiviral therapy decision in chronic hepatitis B with alanine aminotransferase

BackgroundAt present, most assessments of liver fibrosis staging mainly focus on non-invasive diagnostic methods. This study aims to construct a noninvasive model to predict liver histology for antiviral therapy in chronic hepatitis B (CHB) with alanine aminotransferase (ALT) < 2 times upper limit of normal (ULN).MethodsWe retrospectively analyzed 577 patients with CHB who received liver biopsy and whose ALT was less than 2 ULN. Then they were randomly divided into a training group and a validation group. Through logistic regression analysis, a novel predictive model was constructed in the training group to predict significant changes in liver histology [necro-inflammatory activity grade (G) ≥ 2 or fibrosis stage (S) ≥ 2] and then validated in the validation group.ResultsIf liver biopsy showed moderate or severe inflammation or significant fibrosis, antiviral treatment was recommended. Aspartate aminotransferase (AST), anti-hepatitis B virus core antibody (anti-HBC) and glutamine transpeptidase (GGT) were identified as independent predictors for antiviral therapy, with area under the ROC curve (AUROC) of 0.649, 0.647 and 0.616, respectively. Our novel model index, which combined AST, anti- HBC and GGT with AUROC of 0.700 and 0.742 in training set and validation set.ConclusionsThis study established a noninvasive model to predict liver histology for antiviral treatment decision in patients with CHB with ALT < 2 ULN, which can reduce the clinical needs of liver biopsy.

SUN-506 Hyperthyroidism Induced Hepatic Apoptosis

Background:Graves’ disease is commonly associated with abnormal liver function tests, most frequently ALP, but the exact mechanism is not fully understood. In vitro and in vivo animal studies have shown elevated T3 activity can induce hepatocyte apoptosis via a mitochondrial-mediated pathway. This case demonstrates a patient with elevated aminotransferases and hepatic apoptosis most likely secondary to severe hyperthyroidism.Clinical Case:50 year old female with a past medical history of migraines was seen by primary care for fatigue and 15 lb weight loss in one month. She was found to be hyperthyroid with TSH < 0.1 uIU/L (n=0.34-5.6), free T4 3.48 ng/dL (n=0.58-1.64) and mildly elevated aminotransferases of AST 77 IU/L (n=15-41), ALT 144 IU/L (n=12-63), which increased within a week to 159 IU/L and 309 IU/L respectively. ALP and bilirubin were within normal range. She was started on methimazole 20 mg twice daily by her PCP. The patient developed vomiting and stopped taking methimazole after 3-4 days. Upon initial presentation to endocrine clinic, found to be clinically hyperthyroid and as LFTs were improved but still elevated, she was re-challenged with methimazole at a lower dose as well as started on a beta blocker and cholestyramine. TT3 checked was elevated at 2.10 ng/mL (n 0.87-1.78). Graves’ disease was confirmed with elevated TSI as well as RAI uptake and scan showing increased homogenous uptake.She had extensive workup for another etiology by hepatology including autoimmune, which were negative. Her fibrosis score was stage F1-F2 (n=F0) and necroinflammatory activity grade A3 indicating severe activity (n=grade A0). Core needle biopsy of the liver showed focal lytic necrosis/apoptosis and abundant pigment-laden Kupffer cells signifying recent hepatocellular injury. Her AST and ALT down trended and normalized with repeat fibrosis score of F1 and necroinflammatory activity grade A0. She eventually had definitive therapy with RAI treatment. Conclusion: In most cases of hyperthyroid induced liver dysfunction, liver histology showed fatty infiltration, cytoplasmic vacuolization, nuclear irregularity and hyperchromatism.This case, without any other known causes that could explain her hepatic injury, indicates the possible role of hyperthyroidism in hepatic apoptosis.

Two-Dimensional-Shear Wave Elastography with a Propagation Map: Prospective Evaluation of Liver Fibrosis Using Histopathology as the Reference Standard.

ObjectiveThe aim of this study was to prospectively evaluate whether liver stiffness (LS) assessments, obtained by two-dimensional (2D)-shear wave elastography (SWE) with a propagation map, can evaluate liver fibrosis stage using histopathology as the reference standard.Materials and MethodsWe prospectively enrolled 123 patients who had undergone percutaneous liver biopsy from two tertiary referral hospitals. All patients underwent 2D-SWE examination prior to biopsy, and LS values (kilopascal [kPa]) were obtained. On histopathologic examination, fibrosis stage (F0–F4) and necroinflammatory activity grade (A0–A4) were assessed. Multivariate linear regression analysis was performed to determine the significant factors affecting the LS value. The diagnostic performance of the LS value for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis, and the optimal cut-off value was determined by the Youden index.ResultsReliable measurements of LS values were obtained in 114 patients (92.7%, 114/123). LS values obtained from 2D-SWE with the propagation map positively correlated with the progression of liver fibrosis reported from histopathology (p < 0.001). According to the multivariate linear regression analysis, fibrosis stage was the only factor significantly associated with LS (p < 0.001). The area under the ROC curve of LS from 2D-SWE with the propagation map was 0.773, 0.865, 0.946, and 0.950 for detecting F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The optimal cut-off LS values were 5.4, 7.8, 9.4, and 12.2 kPa for F ≥ 1, F ≥ 2, F ≥ 3, and F = 4, respectively. The corresponding sensitivity and specificity of the LS value for detecting cirrhosis were 90.9% and 88.4%, respectively.ConclusionThe LS value obtained from 2D-SWE with a propagation map provides excellent diagnostic performance in evaluating liver fibrosis stage, determined by histopathology.

Shear-Wave Dispersion Slope from US Shear-Wave Elastography: Detection of Allograft Damage after Liver Transplantation.

Background Allograft damage (hepatic parenchymal damage) after liver transplant is associated with the degree of necroinflammation in graft liver. According to a recent animal study, shear-wave dispersion slope obtained at US shear-wave elastography (SWE) is associated with necroinflammatory activity in the liver. Purpose To evaluate the role of shear-wave dispersion slope in detecting allograft damage after liver transplant. Materials and Methods In this prospective study, 104 liver transplant recipients underwent percutaneous liver biopsy for allograft evaluation from December 2017 to November 2018. All participants underwent allograft SWE examination just before liver biopsy, and liver stiffness and shear-wave dispersion slope were obtained. Allograft damage was diagnosed by histopathologic analysis. Clinical and imaging factors related to liver stiffness and shear-wave dispersion slope were determined by multivariable linear regression analysis. Diagnostic performance of each variable in detecting allograft damage was evaluated by comparing area under the receiver operating curve (AUC) values. Results There were 104 study participants (35 women); median age was 56 years (interquartile range, 50-62 years). Allograft damage was found in 46 of 104 (44.2%) of participants. The median liver stiffness (8.2 kPa vs 6.3 kPa; P < .01) and shear-wave dispersion slope (14.4 [m/sec]/kHz vs 10.4 [m/sec]/kHz; P < .01) were higher in participants with allograft damage than in those without damage, respectively. Fibrosis stage was the only determinant factor for liver stiffness (coefficient, 1.8 kPa per fibrosis stage; 95% confidence interval: 0.1, 3.5; P = .03), whereas both fibrosis stage (coefficient, 1.4 [m/sec]/kHz per fibrosis stage; 95% confidence interval: 0.3, 2.6; P = .02) and necroinflammatory activity (coefficient, 1.6 [m/sec]/kHz per necroinflammatory activity grade; 95% confidence interval: 0.5, 2.7; P < .01) affected shear-wave dispersion slope. The AUC for shear-wave dispersion slope in detecting allograft damage was 0.86, which was higher than that of liver stiffness (AUC, 0.75; P < .01). Conclusion Shear-wave dispersion slope determined at US shear-wave elastography may help in detecting allograft damage after liver transplant. © RSNA, 2019 Online supplemental material is available for this article.

Usefulness of noninvasive shear wave elastography for the assessment of hepatic fibrosis in dogs with hepatic disease.

BackgroundTwo‐dimensional shear wave elastography (2D‐SWE) can noninvasively evaluate hepatic elastic modulus as shear wave velocity (SWV). Additionally, it may predict the presence of clinical relevant hepatic fibrosis (≥F2) in dogs with hepatic disease.ObjectivesTo investigate whether SWV measured by 2D‐SWE can differentiate between dogs with (≥F2) and without (F0‐1) clinically relevant hepatic fibrosis.AnimalsTwenty‐eight client‐owned dogs with hepatic disease and 8 normal healthy Beagle dogs were enrolled.MethodsIn this cross‐sectional prospective study, SWVs were measured using 2D‐SWE in all dogs. Hepatic fibrosis stages and necroinflammatory activity grades were histopathologically evaluated using a histological scoring scheme that was adapted from the Ishak schema used in human medicine.ResultsMedian SWVs were significantly higher in dogs with clinically relevant hepatic fibrosis (2.04 m/s; range, 1.81‐2.26 m/s) than in healthy dogs (1.51 m/s; range, 1.44‐1.66 m/s; P = .007), and dogs without clinically relevant hepatic fibrosis (1.56 m/s; range, 1.37‐1.67 m/s; P < .001). However, no significant difference was found in the SWVs between dogs without clinically relevant hepatic fibrosis and healthy dogs (P = .99). Furthermore, median SWVs were not significantly different among dogs with necroinflammatory activity, those without necroinflammatory activity, and healthy dogs (Kruskal‐Wallis test, P = .12).Conclusions and Clinical ImportanceThe 2D‐SWE may be useful for predicting the presence of hepatic fibrosis in dogs with hepatic disease.

Prediction of hepatic necroinflammatory activity in patients with chronic hepatitis B by a simple noninvasive model

BackgroundA model was constructed using clinical and serum variables to discriminate between chronic hepatitis B (CHB) patients with and without significant necroinflammatory activity (score 4–18 vs. score 0–3).MethodsConsecutive CHB patients who underwent liver biopsy were divided into two sequential groups: a training group (n = 401) and a validation group (n = 401). Multivariate analysis identified alanine aminotransferase, γ-glutamyltransferase, prothrombin time and albumin as independent predictors of necroinflammatory activity.ResultsThe area under the receiver operating characteristic curve was 0.826 for the training group and 0.847 for the validation group. Using a cut-off score of H ≤ 0.375, significant necroinflammatory activity (score 4–18) was excluded with high accuracy [78.2% negative predictive value (NPV), 72% positive predictive value (PPV), and 90.8% sensitivity] in 238 (59.4%) of 401 patients in the training group and with the same certainty (88.1% NPV, 61.2% PPV, and 95.1% sensitivity) among 204 (50.9%) of 401 patients in the validation group. Similarly, applying a cut-off score of H > 0.720, significant necroinflammatory activity was correctly identified with high accuracy (90.8% PPV, 57.7% NPV, and 92.0% specificity) in 150 (37.4%) of 401 patients in the training group and with the same certainty (91.8% PPV, 64.6% NPV, and 95.4% specificity) in 188 (46.9%) of 401 patients in the validation group.ConclusionsA predictive model based on easily accessible variables identified CHB patients with and without significant necroinflammatory activity with a high degree of accuracy. This model may decrease the need for liver biopsy for necroinflammatory activity grading in 72.1% of CHB patients.

ADAR1 polymorphisms are related to severity of liver fibrosis in HIV/HCV-coinfected patients

The adenosine deaminase acting on RNA (ADAR1) gene is an interferon-stimulated gene involved in liver injury protection. Our aim was to analyze the association of polymorphisms within this gene with the severity of liver disease in European HIV/HCV-coinfected patients. We performed a cross-sectional study in 220 patients that underwent a liver biopsy. Five SNPs in the ADAR1 gene (rs1127326, rs1127317, rs1127314, rs1127313, rs2229857) were genotyped by GoldenGate assay. The outcome variables were fibrosis stage and necroinflammatory activity grade by METAVIR-score, aspartate aminotransferase to platelet ratio index (APRI), FIB-4 index, and fibrosis progression rate (FPR). In multivariate analysis, fibrosis progression rate (FPR) (aAMRs = 0.97) decreased in a dose-dependent manner with the presence of rs2229857_T, rs1127313_G, rs1127314_G and rs1127317_G; while rs1127326_T allele had only significant associations with FIB-4 (aAMRs ≤ 0.63) and FPR (aAMRs ≤ 0.97). Moreover, carriers of rs2229857_T, rs1127314_G, rs1127317_G, and rs1127326_T alleles were protected against advanced fibrosis (F ≥ 3) (adjusted ORs (aORs) ≤ 0.44), APRI ≥ 1.5 (aORs ≤ 0.33), and FPR ≥ 0.075 (aORs ≤ 0.45). rs1127313_G carriers showed lower odds of having F ≥ 3 (aORs = 0.39), FIB4 ≥ 3.25 (aOR = 0.22) and FPR ≥ 0.075 (aORs = 0.44). In conclusion, ADAR1 polymorphisms protected against severe liver disease in HIV/HCV-coinfected patients. These results could be used to improve therapeutic decision-making in clinical practice.

Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

IntroductionChronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients.MethodsNIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0–2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates.ResultsSeven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74).ConclusionThe identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

Disease severity and erythropoiesis in chronic hepatitis C.

The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients. The red blood cell (RBC) components, serum erythropoietin (EPO) levels, and their relationship to clinical characteristics were evaluated between 124 age-matched and sex-matched healthy controls and 248 histology-proven CHC patients. Chronic hepatitis C patients had significantly higher serum levels of EPO (1.44 ± 0.36 log mIU/mL versus 1.03 ± 0.31 log mIU/mL, P < 0.0001) and lower hemoglobin (Hb) concentrations (14.6 ± 1.4 g/dL versus 15.3 ± 1.2 g/dL, P < 0.001) as compared with healthy controls. Among the CHC patients, the serum EPO level was negatively associated with the Hb concentration (β = -0.227; 95% confidence intervals [CI]: -0.09-0.027; P < 0.001) and RBC counts (β = -0.204; 95% CI: -0.245-0.061; P = 0.001) and was positively correlated with necroinflammatory activity (β = 0.201; 95% CI: 0.009-0.046; P = 0.003) and fibrosis (β = 0.143; 95% CI: 0.003-0.076; P = 0.04) of liver histopathology. For non-cirrhotic CHC patients, the severity of liver necroinflammatory activity was positively correlated with the reticulocyte and serum EPO levels (P = 0.001 and 0.008, respectively), and negatively related to the RBC counts (P = 0.03). Using stepwise multivariate linear regression analysis, the grade of necroinflammatory activity was positive (β = 0.214; 95% CI: 0.046-0.209, P = 0.002), whereas the Hb concentration was inversely (β = -0.205; 95% CI: -0.09-0.018, P = 0.004) associated with the serum EPO levels in CHC patients. The disease activity in CHC patients had a negative impact on erythropoiesis with compensatory higher but blunted EPO responses.

A noninvasive model to predict liver histology in HBeAg-positive chronic hepatitis B with alanine aminotransferase ≤ 2upper limit of normal.

Liver biopsy remains the gold standard to evaluate liver histology. However, it has several limitations. This study aims to construct a noninvasive model to predict liver histology for commencing antiviral therapy in HBeAg-positive chronic hepatitis B (CHB) with aminotransferase (ALT) ≤ 2 upper limit of normal (ULN). Two hundred and ninety-eight patients with HBeAg-positive CHB, ALT ≤ 2ULN and HBV-DNA ≥20 000 IU/ml were enrolled and randomly divided into a training group and a validation group. A noninvasive model was constructed in the training group to predict significant liver histological change [necroinflammatory activity grade (G) ≥ 2 or fibrosis stage (S) ≥ 2] and then validated in the validation group. Aspartate aminotransferase, HBsAg, platelet, and albumin were identified as independent predictors. A model was constructed by them. It had an area under the receiver operating characteristic curve of 0.875 in the training group, 0.858 in the validation group and 0.868 in the entire cohort. Using a cut-off point of -0.96, it showed 93% sensitivity, 90% negative predictive value (NPV) in the training group and 95% sensitivity, 94% NPV in the validation group. Using a cut-off point of 0.96, it showed 95% specificity, 91% positive predictive value (PPV) in the training group and 89% specificity, 80% PPV in the validation group. This study constructed a noninvasive model to predict liver histology in HBeAg-positive CHB with ALT ≤ 2ULN, which might reduce the clinical need for liver biopsy.

Diagnostic Accuracy of Controlled Attenuation Parameter for Detecting Hepatic Steatosis in Patients with Chronic Liver Disease

Introduction: Controlled attenuation parameter (CAP), measured by transient elastography, has been suggested as a noninvasive method for the detection and quantification of steatosis. We aimed to assess the accuracy of CAP to detect steatosis in patients with chronic liver disease (CLD) compared with liver histology and to evaluate factors that correlate with the CAP value. Methods: Patients with CLD who underwent liver biopsy and simultaneous CAP determination were consecutively enrolled. CAP was measured using the M probe of FibroScan® (Echosens, Paris, France). Histologically, steatosis was categorized as absent (S0: <5%), mild (S1: 5-33%), moderate (S2: 34-66%) and severe (S3: >66% of all hepatocytes). Results: We analyzed 159 patients with CLD (61% men, mean age 47.9 ± 12.9 years). We found a positive correlation between CAP and steatosis in histology (r_s = 0.869, p < 0.001), arterial hypertension (r_s = 0.222, p = 0.005), type 2 diabetes mellitus (r_s = 0.279, p < 0.001), body mass index (BMI; r_s = 0.533, p < 0.001), total cholesterol (r_s = 0.442, p < 0.001), triglycerides (r_s = 0.272, p = 0.001), and non-alcoholic fatty liver disease (NAFLD; r_s = 0.588, p < 0.001). In the multivariate analysis, BMI >25 (odds ratio [OR] 48.4, 95% confidence interval [CI] 23.78-72.95, p < 0.001), serum total cholesterol (OR 3.803, 95% CI 2.203-13.889, p = 0.008), and NAFLD etiology (OR 40.8, 95% CI 15.01-66.66, p = 0.002) were independently associated with higher CAP values. We did not find any significant correlation between CAP and the grade of necroinflammatory activity (r_s = 0.063, p = 0.808) or fibrosis (r_s = 0.071, p = 0.713) in histology and with alanine aminotransferase (r_s = 0.190, p = 0.356) or aspartate aminotransferase (r_s = 0.117, p = 0.142). Optimal CAP cutoff values for detecting steatosis ≥S1, ≥S2, and ≥S3 were 206.5, 232.5, and 282.5 dB/m, respectively. CAP performance was 0.822, 0.956, and 0.976 for diagnosing steatosis ≥S1, ≥S2, and ≥S3, respectively. Conclusions: CAP had an excellent diagnostic accuracy for the detection of steatosis in diverse CLD patients. A CAP value cutoff of <282.5 dB/m excludes severe steatosis ≥S3 with an accuracy of 98%.

Diffusion kurtosis imaging and diffusion-weighted imaging in assessment of liver fibrosis stage and necroinflammatory activity.

To investigate and compare the diagnostic value of diffusion kurtosis imaging (DKI) with diffusion-weighted imaging (DWI) in assessing and quantifying hepatic fibrosis. Thirty rats were divided into the control group (n=6) and the fibrosis experimental groups (n=6 per group) with CCl4 administration for 2, 4, 6, and 8 weeks. Liver fibrosis stage (S) and necroinflammatory activity grade (G) were histopathologically determined. DKI and DWI were performed; mean apparent diffusion (MD), mean kurtosis (MK), and apparent diffusion coefficient (ADC) values were calculated. DKI parameters were compared with ADC values according to G/S scores. Strong inverse correlations were found between the degree of fibrosis and both MD and ADC (r=-0.840 and r=-0.760), while only weak correlation existed in MK (r=0.405). ROC analyses demonstrated the AUC in MD, MK, and ADC of 0.862, 0.684, 0.817 for identifying mild and severe fibrosis, and 0.757, 0.675, 0.733 for non-cirrhosis and cirrhosis, respectively. The degree of fibrosis was significantly correlated with α-smooth muscle actin (α-SMA) (P<0.0001); α-SMA had strong inverse correlation with MD (r=-0.723), moderate inverse correlation with ADC (r=-0.613), and very weak correlation with MK (r=0.175). Additionally, MD was strongly correlated with the necroinflammatory activity (r=-0.758), ADC was moderately correlated (r=-0.492), and MK was weakly correlated (r=0.254). DKI may provide added information and serve as a valuable tool for the characterization and surveillance of liver fibrosis in a non-invasive manner.

Liver fibrosis staging using T1 mapping on gadoxetic acid-enhanced MRI compared with DW imaging

To evaluate the utility of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for staging liver fibrosis. This retrospective study was approved by the institutional review board and included 145 patients (mean age: 54 years old; 115 men and 30 women). Necro-inflammatory activity grade (G) and liver fibrosis stage (S) were histopathologically determined. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured and the reduction rate of the T1 relaxation time (Δ%) was calculated. T1 relaxation time measurements were compared with ADC values according to S/G scores. Unenhanced hepatobiliary phase (HBP) and Δ% of T1 relaxation times showed significant correlations with S/G scores (rho: 0.28, 0.51, -0.35 for the S score, 0.26, 0.39, -0.26 for the G score, respectively, p<0.05). ADC values showed significant correlation with the S score (rho: -0.17, p = 0.04) and did not correlate significantly with the G score (rho: -0.07, p = 0.39). The areas under receiver operator characteristics (AUC) curve of unenhanced HBP, Δ% T1 relaxation time, and the ADC value were 0.68, 0.82, 0.71, 0.61 for the identification of S ≥ 3, and 0.63, 0.68, 0.62, 0.52 for the identification of G ≥ 3, respectively. The HBP T1 relaxation time was better than that of ADC for identification of S ≥ 3 (p = 0.0005) and G ≥ 3 (p = 0.014). The HBP T1 relaxation time measurement on gadoxetic acid-enhanced MRI images might be a potential biomarker in the staging of hepatic fibrosis, and was more accurate than the ADC measurement.

Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. At present, there is no appropriate histologic scoring system available for PSC, evaluating both degree of necroinflammatory activity (grade) and fibrosis (stage). The aim of this study was to assess if three scoring systems, commonly used in different liver diseases could be applied for grading and/or staging of PSC. Sixty-four PSC patients from a Dutch cohort, who underwent diagnostic liver biopsy, were included. Staging was scored using Ishak, Nakanuma, and Ludwig systems. Grading was scored using Ishak and Nakanuma systems. Three measures of outcome were defined; transplant-free survival, time to liver transplantation (LTx) and occurrence of cirrhosis related symptoms (CRS). Association of grade and stage with outcome was estimated using Kaplan-Meier log-rank test, and Cox regression analysis. Correlation with biochemistry was assessed by Spearman's rank test. There were strong associations between disease stage measured by Ishak, Nakanuma, and Ludwig staging systems with both outcome measuring transplant-free survival (Hazard ratio (HR) 2.56; 95% CI 1.11-5.89, HR 6.53; 95% CI 2.01-21.22, HR 1.94; 95% CI 1.00-3.79, respectively), and time to LTx (HR 4.18; 95%CI 1.51-11.56, HR 7.05; 95% CI 1.77-28.11, HR 3.13; 95%CI 1.42-6.87, respectively). Ishak and Nakanuma grading systems were not associated with CRS. Weak correlations between histopathology and liver biochemistry were shown. Applying the Nakanuma, Ishak, and Ludwig histopathological staging systems is feasible and clinically relevant given their association with transplant-free survival and time to LTx. This suggests that these staging systems could be likely candidates for surrogate endpoints and stratification purposes in clinical trials in PSC.

Hepatic progenitor cells in children with chronic hepatitis C: correlation with histopathology, viremia, and treatment response.

Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate towards the hepatocytic and cholangiocytic lineages. Many studies have investigated HPCs in adults with hepatitis C virus infection; however, none has been carried out in the pediatric population. Therefore, this work aimed to investigate HPCs expansion in children with chronic hepatitis C (CHC) and its correlation with histopathology, viremia, and treatment response. Eighty children with CHC, 73 of whom received interferon-based therapy, were recruited. Sections of their liver biopsies were prepared for immunostaining of HPCs using cytokeratin-7 antibody. HPCs were expanded in most children (81.3%) with CHC. Expansion occurred in two forms: intraparenchymal isolated hepatic progenitor cell form and periportal ductular reaction form. There was a significant increase in HPCs expansion in higher stages of fibrosis (50, 81.8, and 100% in no, mild, and moderate fibrosis, respectively, with P=0.029). Also, HPCs expansion increased with increased grade of necroinflammatory activity (0, 77.8, 81.8, and 100%, in no, minimal, mild, and moderate activity, respectively), although this was statistically insignificant. Moreover, a significant positive correlation was found between the isolated hepatic progenitor cell number and ductular reaction grade (r=0.755, P<0.0001), and both were significantly correlated with the level of viremia and the grade of necroinflammatory activity. Finally, HPCs expansion was not related to the treatment response. The relationship of HPCs with both the severity of hepatitis and the stage of fibrosis may be because of a role of HPCs in their pathogenesis.

Hepatitis C related chronic liver cirrhosis: feasibility of texture analysis of MR images for classification of fibrosis stage and necroinflammatory activity grade.

PurposeTo assess the feasibility of texture analysis for classifying fibrosis stage and necroinflammatory activity grade in patients with chronic hepatitis C on T2-weighted (T2W), T1-weighted (T1W) and Gd-EOB-DTPA-enhanced hepatocyte-phase (EOB-HP) imaging.Materials and methodsFrom April 2008 to June 2012, MR images from 123 patients with pathologically proven chronic hepatitis C were retrospectively analyzed. Texture parameters derived from histogram, gradient, run-length matrix, co-occurrence matrix, autoregressive model and wavelet transform methods were estimated with imaging software. Fisher, probability of classification error and average correlation, and mutual information coefficients were used to extract subsets of optimized texture features. Linear discriminant analysis in combination with 1-nearest neighbor classifier (LDA/1-NN) was used for lesion classification. In compliance with the software requirement, classification was performed based on datasets from all patients, the patient group with necroinflammatory activity grade 1, and that with fibrosis stage 4, respectively.ResultsBased on all patient dataset, LDA/1-NN produced misclassification rates of 28.46%, 35.77% and 20.33% for fibrosis staging and 34.15%, 25.20% and 28.46% for necroinflammatory activity grading in T2W, T1W and EOB-HP images. In the patient group with necroinflammatory activity grade 1, LDA/1-NN yielded misclassification rates of 5.00%, 0% and 12.50% for fibrosis staging in T2W, T1W and EOB-HP images respectively. In the patient group with fibrosis stage 4, LDA/1-NN yielded misclassification rates of 5.88%, 12.94% and 11.76% for necroinflammatory activity grading in T2W, T1W and EOB-HP images respectively.ConclusionTexture quantitative parameters of MR images facilitate classification of the fibrosis stage as well as necroinflammatory activity grade in chronic hepatitis C, especially after categorizing the input dataset according to the activity or fibrosis degree in order to remove the interference between the fibrosis stage and necroinflammatory activity grade on texture features.