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Acoustic structure quantification (ASQ) based on the analysis of ultrasound backscattered statistics has been reported to detect liver fibrosis without significant hepatic steatosis. This study proposed using ultrasound parametric imaging based on the parameter α of the homodyned K (HK) distribution for staging liver fibrosis in patients with significant hepatic steatosis. Raw ultrasound image data were acquired from patients (n = 237) to construct B-mode and HK α parametric images, which were compared with the focal disturbance (FD) ratio obtained from ASQ on the basis of histologic evidence (METAVIR fibrosis score and hepatic steatosis severity). The data were divided into group I (n = 173; normal to mild hepatic steatosis) and group II (n = 64; with moderate to severe hepatic steatosis) for statistical analysis through one-way analysis of variance and receiver operating characteristic (ROC) curve analysis. The results showed that the HK α parameter monotonically decreased as the liver fibrosis stage increased (p < .05); concurrently, the FD ratio increased (p < .05). For group I, the areas under the ROC (AUROCs) obtained using the FD ratio and the α parameter (AUROCFD and AUROCα) were, respectively, 0.56 and 0.55, 0.68 and 0.68, 0.64 and 0.64 and 0.62 and 0.62 for diagnosing liver fibrosis ≥F1, ≥F2, ≥F3 and ≥F4. The values of AUROCFD and AUROCα for group II were, respectively, 0.88 and 0.91, 0.81 and 0.81, 0.77 and 0.76 and 0.78 and 0.73 for diagnosing liver fibrosis ≥F1, ≥F2, ≥F3 and ≥F4. As opposed to previous studies, ASQ was found to fail in characterizing liver fibrosis in group I; however, it was workable for identifying liver fibrosis in patients with significant hepatic steatosis (group II). Compared with ASQ, HK imaging provided improved diagnostic performance in the early detection of liver fibrosis coexisting with moderate to severe hepatic steatosis. Ultrasound HK imaging is recommended as a strategy to evaluate early fibrosis risk in patients with significant hepatic steatosis.

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 (≤18 years old) who had undergone both liver 2-D ultrasound SWE and percutaneous liver biopsy within 6 months. 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 11.5 years (interquartile range: 8.0–14.3 years), 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 >1.89 m/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 >1.89 m/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.

After liver transplantation (LT), the role of preformed donor-specific anti-human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case-control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched-control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02-6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33-4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor-specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12-3.49; P = 0.02). Acute antibody-mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1-125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium-term and longterm patient survival. The use of a T or B cell-depleting agent did not reduce the risk of acute rejection.

Background: Liver allograft fibrosis (LAF) is a common challenge threatening patient survival after liver transplantation, making a potent imaging technique vital for clinical management. To date, ultrasound (US) elastography has been regarded as one of the most promising techniques for LAF monitoring. However, it is susceptible to inflammation and insensitive to early-stage pathological changes, which affects its diagnosis accuracy of LAF. Herein, based on a thorough comparison with US elastography at multiple disease stages, VEGFR2-targeted US molecular imaging (USMI) was validated to be highly potent for LAF early diagnosis and staging. Methods: The VEGFR2-targeted microbubbles (MBs) were fabricated as a specific probe for angiogenesis, and a LAF rodent model was induced. Then, VEGFR2-targeted USMI and US elastography were compared in terms of evaluating the LAF progress. Findings: The quantitative USMI result (NID) displayed much higher linear correlation with histological standards including Metavir fibrosis score (R2 = 0.7723 vs 0.3504) and VEGFR2 semi-quantitative counting (IOD) (R2 = 0.7801 vs 0.4902) than US elastography measurements. Interpretation: The results demonstrated a greatly improved diagnosis accuracy owing to the advantages of VEGF receptor-2 (VEGFR2) targeted USMI in reducing the inflammatory influence as well as increasing the sensitivity to early-stage pathological changes. The study overcame the intrinsic limitations of US elastography, thus highlighting the potential of VEGFR2-targeted USMI as an effective monitoring tool for LAF surveilling. Funding: This work was supported by the National Natural Science Foundation of China, Key Research and Development Program of Guangdong Province and Fundamental Research Funds for the Central Universities. Declaration of Interests: The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Ethics Approval Statement: All animal studies in the research were approved by the Sun Yat-sen University Animal Care Committee and followed standard guidelines.

Toll-like receptor 4 (encoded by TLR4 gene) has a variety of functions, including tissue homeostasis, regulation of cell death and survival via activation of signaling pathways which lead to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. TLR4 may have a crucial role in pathogenesis of complex and infectious diseases. Functional polymorphism TLR4 +3725G/C substitution (rs11536889) leads to faster transcript degradation and receptors number decrease. The study investigated TLR4 rs11536889 genotype and allele distribution in healthy volunteers from Ukraine (n = 155), autoimmune hepatitis (AH) children (n = 56) and chronic hepatitis C (CHC) adult patients with various fibrosis severity stages (n = 78). Genotyping was performed by allele-specific PCR. The obtained genotype frequencies in Ukrainian population were: GG genotype—0.813, GC—0.168, CC—0.019 and showed no significant deviation from the ones expected according to Hardy-Weinberg equilibrium. AH and CHC patients were divided according to METAVIR fibrosis score into two groups—with stages F1–F2, and with F3–F4. The frequency of rs11536889 C allele carriers were higher in the group of AH patients with F3–F4 (0.179) comparing to patients with F1–F2 (0.071). This data did not reach the threshold for significance but showed a trend toward association between C allele carriers and higher fibrosis degree. Moreover, the significantly (p < 0.05) higher frequency of C allele carriers was observed in CHC patients with higher fibrosis degree (0.400) compared to patients with lower degree (0.057). Severe liver damage risk in such individuals is 11 increased (OR = 11.11, 95% CI: 2.70–45.66). Thus, TLR4 rs11536889 C allele is associated with higher level of fibrotic liver damage in patients with chronic hepatitis.

Pentraxin 3 (PTX3) plays a pathogenic role in experimental models of chronic liver injury and contributes to the progression of fibrosis. The detection of advanced fibrosis (METAVIR F≥3) is important to identify patients who are in urgent need of antiviral treatments versus those whose treatment could be deferred (F≥2). The aim was to assess the diagnostic value of PTX3 as a potential biomarker for clinically significant and advanced fibrosis. PTX3 associations with biochemical and histological parameters of inflammatory activity and fibrosis were investigated in 138 patients with chronic viral hepatitis C (HCV) before antiviral treatment. METAVIR histological scores of activity and fibrosis were obtained. PTX3 was measured by enzyme-linked immunosorbent assay. The diagnostic accuracy of serum PTX3 levels was compared to that of other fibrosis markers, including transforming growth factor‐β1 (TGF-β1), hyaluronic acid (HA), aspartate transaminase to platelet ratio index (APRI), fibrosis score based on four factors (FIB4), gamma-glutamyltranspeptidase to platelet ratio (GPR), and the liver stiffness measurement (LSM) by transient elastography (FibroScan®). In HCV patients the PTX3 level increased in parallel with the METAVIR histological score of activity, being independently associated with the METAVIR fibrosis score (P < 0.001). Using the receiver operating characteristics analysis, the best marker for detecting F≥2 and F≥3 was PTX3 with AUC = 0.802 and AUC = 0.867, respectively. The area under the curve of PTX3 for predicting significant fibrosis (F≥2) was significantly greater than those for the GPR ratio (AUC = 0.648) and FIB-4 score (AUC = 0.770) and similar to that for APRI index (AUC = 0.831). PTX3 provided clinically relevant diagnostic accuracy as a single marker of significant fibrosis.

Background: Acoustic radiation force impulse (ARFI) imaging is a popular modality to measure liver fibrosis. ARFI selects optimal locations for measurement under imaging guiding. However, there are concerns on study locations and observers bias. To decrease the variations, ARFI at two locations was measured with standardized protocol. This study attempted to establish its cutoff values according to Metavir fibrosis score in different etiologies. Methods: A consecutive series of patients who received liver histology study were prospectively enrolled. All cases had hemogram, liver biochemistry, viral markers, and ARFI two-location measurements within 4 weeks of histology study. A standardized protocol was performed by single technologist. We excluded patients with alanine aminotransferase >5x upper limit normal. Results: Five hundred and ten patients that included 153 seronegative for both HBsAg and anti-HCV Non-B non-C (NBNC), 33 autoimmune liver diseases (AILD), 261 chronic hepatitis B (CHB), and 63 chronic hepatitis C (CHC) were enrolled. About 83% of NBNC patients had fat cell >5%. For diagnosis of liver cirrhosis, the area under receiver operating characteristic curve of NBNC, AILD, CHB, and CHC groups was 0.937, 0.929, 0.784, and 0.937; the cutoff values for mean ARFI were 1.788, 2.095, 1.455, and 1.710 m/s, respectively. The sensitivity and specificity are both over 0.818 for patients with nonalcoholic fatty liver diseases, CHC, and AILD, but the corresponding data are only 0.727–0.756 in CHB. The Fibrosis-4 Score is as good as ARFI on fibrosis assessment in NBNC. Conclusion: The performance of ARFI two-location measurement is excellent in NBNC, AILD, and CHC, but is only satisfactory in CHB.

Background and Aim Over the last decade, the development of liver stiffness measurement using transient elastography (FibroScan®) and its widespread use has become the standard for non-invasive staging of liver fibrosis. Our study explores a real-life experience on concordance of fibrosis staging between the fibroscan and the liver biopsies aiming to assess its reliability. Method We conducted a retrospective study between September 2014 and May 2019 comparing fibroscan and liver biopsy findings. The FibroScan 502 Touch results were interpreted to give the Metavir fibrosis score. Where necessary, the Ishak score of the histology samples was converted to a Metavir equivalent. Discordance was defined as a difference of ≥ 2 stages between the two modalities of staging fibrosis and was analysed using the Chi square test. We analysed the data within a one year duration between the fibroscan and liver biopsy. Results During the study period, an overall total of 199 liver biopsies and 1218 fibroscans were undertaken. Twenty-five patients had both a fibroscan and a liver biopsy performed within a one year interval. The mean and median interval between fibroscan and biopsy was 42 and 28 days respectively. The median fibroscan stage was F3 (range 0–4) and the median liver biopsy stage was F1 (range 0–4). When compared to the liver biopsy, an identical fibroscan based fibrosis score was obtained in 4 (16%) cases. Fibroscan had understaged 2 (8%) and over staged 19 (76%) cases while discordance was noted in 12 (48%) cases (figure 1). Discordance was not statistically different for F0-1 in comparison to F2-4 scores (p=0.311), however, fibroscan score of F0-1 was significantly more likely to have identical value of Metavir score for both fibroscan and liver biopsy (p=0.009) (figure 1). Conclusion Fibroscan with lower fibrosis scores (F0-1) had higher concordance to the liver biopsy based histological staging and therefore can be used safely to exclude significant fibrosis. Moderate to severe fibrosis staging (F2-4) showed increased disparity between the biopsies and the fibroscan scores, with the latter usually over-staging the level of fibrosis. We therefore feel fibroscan in isolation may not be suitable to diagnose advanced liver fibrosis.

BACKGROUND AND AIM Serum Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel fibrosis marker for various chronic liver diseases. We investigated the ability of M2BPGi to predict liver fibrosis in liver transplant (LT) recipients. METHODS A total of 116 liver biopsies were performed in 113 LT recipients. The serum level of M2BPGi was also measured on the same day. The median age at LT and liver biopsy was 1.1 and 11.8 years, respectively. Serum M2BPGi levels and liver fibrosis status using METAVIR fibrosis score were compared. Immunohistological evaluation by anti-α-smooth-muscle actin (αSMA) was performed, and the relationship between αSMA positive rate and serum M2BPGi levels was investigated. RESULTS The median M2BPGi level was 0.78 (range, 0.22-9.50), and 65, 29, 16, 5, and 1 patient(s) had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F0 fibrosis, median M2BPGi level was 0.69 and was significantly lower than in patients with F1 (median 0.99, P F1: 0.716, > F2: 0.720, and > F3: 0.900. Three patients with acute cellular rejection showed high levels of M2BPGi, which decreased after the treatment. A positive correlation existed between M2BPGi levels and αSMA positive rate (r2 = 0.715, P

Background chronic viral infections by both HCV and HIV may lead to polyclonal activation of B cells resulting in hypergammaglobulinemia. This study retrospectively analyzed the effect of HCV eradication with interferon-free direct-acting antiviral agents (DAAs) on the gamma globulin levels in HCV-infected patients with or without HIV coinfection to identify factors potentially associated with gamma globulins decrease. Methods The charts of patients treated with DAAs for HCV chronic infection between January 2015-June 2019 were retrospectively reviewed. Gamma globulin levels before treatment and 12 weeks after the end of anti-HCV therapy were evaluated along with liver tests, liver fibrosis stage by elastography, SVR achievement, HIV-coinfection. Multivariate analyses were carried out to assess the factors and the potential confounders related to the changes in gamma globulin levels. Results A significant decrease of gamma globulin concentration was found in both cirrhotic and non-cirrhotic HCV-infected patients after treatment (from mean ± SD of 1.5 ± 0.44 g/dL to 1.31 ± 0.37 g/dL; p = 0.0001). Adjusted linear regression analyses of serum gamma globulin changes from baseline to SVR12 showed a positive significant association with pre-treatment gamma-globulin levels (β-coefficient −0.23; p = 0.0001), Metavir fibrosis score (β-coefficient -0.74; p = 0.008), ALT values and baseline HCV-RNA levels > 800,000. No difference was found between HIV-infected and HIV-uninfected patients. Conclusions Our study confirms previous preliminary observation of the decrease of serum gamma globulins after HCV eradication either achieved with interferon-based therapy or with DAAs, suggesting a leading role of the virus on the activation of B cell compartment and gamma globulins production.

BACKGROUND: Fibrosis are common structural hepatic change in patients with chronic hepatitis. Liver biopsy is the gold standard for determining the extent of liver fibrosis. Considering the technical difficulties and cost, improvements in non-invasive screening tools are greatly needed. Bioimpedance have been shown to be safe to evaluate tissue fibrosis. OBJECTIVE: To assess the utility of using monofrequential bipolar bioimpedance for the detection of severity of liver fibrosis consistent with chronic viral hepatitis C infections. METHODS: One hundred and ten patients were studied prospectively and formed two groups according to the lab tests results for the detection of HCV, ALT and AST: Group 1 Control (n=50 healthy patients with HCV negative and with ALT and AST values within the normal clinical range) and Group 2 Positive (n=60 patients positive for anti-HCV positive) which were biopsied. All patients underwent an examination with an Electro Sensor Complex, bioimpedance technology. To compare the groups 1 and 2, the ROC curves was used to determine the specificity and sensitivity of the bioimpedance to detect liver fibrosis. To identify liver fibrosis severity the Group 2 Positive was subdivided according to the liver biopsy results (Metavir fibrosis score) into: Sub Group 2A (F0-F1 n=25) - patients without or with minimal portal fibrosis and Sub Group 2B (F3-F4 n=20) patients with numerous septa/cirrhosis. A statistical analysis was conducted to analyze the bioimpedance data differences in delta of the conductance. RESULTS: From the comparison between Groups 1 and 2: 1) The delta value for conductance in the pathway representing the right foot-left hand minus left hand-right foot demonstrated a sensitivity of 85% and a specificity of 78% with a cutoff value ≤5 and P=0.0001. 2) For the comparison between Sub Group 2A (Metavir F0+F1) and Sub Group 2B (Metavir F3+F4), the neural network for the Electro Sensor Complex data demonstrated a sensitivity of 85% and a specificity of 72% with a cutoff probability >50% and P=0.001. AUCROC=0.81. CONCLUSION: Bioimpedance technology had good level sensitivity and acceptable specificity for detecting liver fibrosis using delta of the conductance. There is a potential for the use of bioimpedance technology as non-invasive approaches for screening of liver fibrosis. RESUMO CONTEXTO: A fibrose é uma alteração hepática estrutural comum em pacientes com hepatite crônica. A biópsia hepática é o padrão ouro para determinar a extensão da fibrose hepática. Considerando as dificuldades técnicas e os custos, melhorias em ferramentas de rastreio não-invasivas são bastante necessárias. A tecnologia bioimpedância tem se mostrado ser segura para avaliar fibrose tecidual. OBJETIVO: Avaliar a utilidade do uso da bioimpedância bipolar para detectar a severidade da fibrose hepática compatível com a hepatite viral B e C. MÉTODOS: Cento e dez pacientes foram estudados, prospectivamente e dois grupos foram formados de acordo com os resultados dos testes laboratoriais para a detecção de HCV, ALT e AST: Grupo 1 Controle (n=50 pacientes saudáveis com HCV negativos e com valores de ALT e AST dentro do padrão de normalidade) e Grupo 2 Positivo (n=60 pacientes positivos para a infecção viral anti-VHC ou HBsAg positiva) que foram biopsiados. Todos os pacientes foram submetidos a um exame com o Electro Sensor Complex, que utiliza a bioimpedância bipolar. Para comparar os Grupos 1 e 2, a curva ROC foi utilizada para determinar a especificidade e sensibilidade da bioimpedância em detectar a fibrose hepática. Para identificar a severidade da fibrose hepática, o Grupo 2 Positivo foi subdividido de acordo com os resultados da biópsia (escore Metavir) em: Sub Grupo 2A (F0-F1 n=25 ) - pacientes sem ou com fibrose portal mínima e Sub Grupo 2B (F3-F4 n=20) pacientes com numerosos septos/cirrose. A análise estatística foi realizada para analisar as diferenças dos valores delta de condutância da bioimpedância. RESULTADOS: A comparação entre os Grupos 1 e 2 mostrou: 1) O valor delta de condutância na via do pé direito à mão esquerda menos o valor do delta da mão esquerda ao pé direito demonstrou uma sensibilidade de 85% e uma especificidade de 78%, com um valor de corte ≤5 e P=0,0001. 2). Na comparação entre o Sub Grupo 2A (Metavir F0+F1) e o Sub Grupo 2B (Metavir F3 + F4), a rede neural para os dados aferidos pelo Electro Sensor Complex demonstrou uma sensibilidade de 85% e uma especificidade de 72%, com um corte de probabilidade >50% P=0,001 e AUCROC=0,81. CONCLUSÃO: Bioimpedância apresentou boa sensibilidade e aceitável especificidade para a detecção da fibrose hepática utilizando o delta da condutância da bioimpedância. Existe um potencial para o uso da bioimpedância como abordagens não-invasivas para o rastreamento da fibrose hepática.

Background & Aims The diagnostic accuracy of a novel serological panel (BioFibroScore®) to predict hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection is unknown. Methods Three markers of BioFibroScore®, including urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and beta-2 microglobulin (β2M), were retrospectively evaluated in 635 HCV-infected patients who received percutaneous liver biopsy and FibroScan®. The formula of BioFibroScore® to predict the severity of hepatic fibrosis was developed by Adaboost algorithm. The diagnostic accuracy of hepatic fibrosis was assessed both for BioFibroScore® and FibroScan®, taking METAVIR fibrosis score as the reference standard. Results uPA and β2M were positively and MMP-9 was negatively associated with the severity of hepatic fibrosis. Thirty-five (5.5%) patients had failed FibroScan® assessment. By Adaboost model for BioFibroScore® and the established reference ranges for FibroScan®, 85.7% and 89.0% of the patients had an identical result for F0-1, F2, F3 and F4, as compared to liver biopsy. The concordance rate between BioFibroScore® and FibroScan® was 80.7%. BioFibroScore® overestimated and underestimated the stage of hepatic fibrosis in 8.3% and 6.0% patients, and most patients had one stage error. Among patients with failed FibroScan® assessment, 82.9% of them were correctly diagnosed by BioFibroScore®. Bootstrap analysis for BioFibroScore® showed the diagnostic accuracy was 80.9-88.4%. Conclusions BioFibroScore® is accurate to assess the stage of hepatic fibrosis in HCV-infected patients. Applying this noninvasive test can substantially reduce the need for invasive liver biopsy and can play a role for fibrosis evaluation when FibroScan® assessment was unavailable or unreliable.

BACKGROUND: HCC in Egypt usually occurs in HCV cirrhotic livers with poor prognosis due to late diagnosis. High hnRNPK & low Claudin-4 profiles indicate Epithelial Mesenchymal Transition (EMT), malignant transformation and high-grade tumours.AIM: We studied the immunohistochemical expression of hnRNPK and Claudin-4 in HCV induced early HCC (eHCC) and adjacent liver tissue in Egyptian patients to improve eHCC detection in cirrhotic livers with better curative therapy options.METHOD: We studied the immunohistochemical expression of hnRNPK and Claudin-4 in 100 Egyptian patients resection specimens of HCV induced early HCC (eHCC) and adjacent liver tissue, in order to improve eHCC detection in cirrhotic livers, thus improving their therapeutic options.RESULTS: Early HCC grade significantly directly correlated with nuclear hnRNPK/5HPFs count and inversely correlated with Claudin-4 expression %, with a converse correlation between hnRNPK and Claudin-4. Moreover in eHCC, combined hnRNPK ³ 30/5HPFs & Claudin-4 ³ 40% significantly distinguished low grade eHCC (G1) from high grade eHCC (G2&G3), with sensitivity 97% & specificity 69.7% for hnRNPK ³ 30/5HPFs, and with sensitivity 70% & specificity 94.3% for Claudin-4 ³ 40%. Moreover in the adjacent liver, both markers expressions significantly directly correlated with each other and with METAVIR fibrosis score but not with activity. Furthermore, 58% of eHCCs showed hnRNPK ³ 30 Claudin-4 < 40% profile, indicating EMT type3, compared to 26% with hnRNPK ³ 30 Claudin-4 £ 10% profile in adjacent cirrhotic/ precirrhotic liver, with significant use of combined hnRNPK ³30/5HPFs & Claudin 4 £ 10% as eHCC prediction cut offs in cirrhosis (p < 0.05).CONCLUSION: Combination of hnRNPK and Claudin-4 can indicate early HCC development in HCV cirrhotic livers using hnRNPK ³ 30/5HPFs & Claudin-4 £ 10% cut offs. Also, combination of hnRNPK ³ 30/5HPFs & Claudin-4 ³ 40% can distinguish low grade eHCC (G1) from high grade eHCC (G2&G3).

Pediatric liver transplant recipients are at risk of developing graft fibrosis which can affect patient survival. VCTE is a non-invasive tool that measures LSM and has been shown to correlate with hepatic fibrosis. The aim of this study was to therefore evaluate the ability of LSM to predict fibrosis in pediatric liver transplant recipients with different graft types. We performed a cross-sectional study evaluating LSM of 28 pediatric liver transplant recipients who underwent a total of 20 liver biopsies within 1 month of LSM. LSM was compared to liver histology as well as graft type: WL or PL. The median LSM of all post-transplant patients was 5.6 kPa (range = 2.7-18.3). There was a statistically significant correlation between LSM and METAVIR fibrosis score (P = .001) and LAF score (P < .001). There was no difference in LSM between graft type (P = .088). The AUROC curve for LSM predicting any significant fibrosis (F ≥ 2) was 0.863. A cutoff value of 7.25 had a sensitivity of 71%, specificity of 100%, NPV of 87%, and PPV of 100% for significant fibrosis. LSM by VCTE is feasible in pediatric liver transplant recipients regardless of graft type. We found a significant correlation between LSM and hepatic fibrosis and established a cutoff value that may help determine which patients warrant further evaluation for graft fibrosis.

Background and aims Serum GP73 is a useful biomarker in assessing hepatic fibrosis degree. The aim of this study was to evaluate the predictive value of serum GP73 level for posthepatectomy short-term outcomes in hepatocellular carcinoma (HCC) patients. Methods A total of 280 patients undergoing liver resection for HCC between October 2015 and April 2018 were included in this study. Detailed preoperative clinicopathological data were collected and GP73 levels in serum obtained the day before hepatectomy were examined. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff of GP73, and independent risk factors for postoperative outcomes was assessed by logistic regression model. Results The mean GP73 level in patients was 111.8 ± 153.3 ng/mL. Serum GP73 levels were correlated with the METAVIR fibrosis score. Overall complications occurred in 145 patients and major complications developed in 29 patients. ROC analysis demonstrated that the predictive power of serum GP73 for postoperative outcomes was greater than the Child–Pugh score, ALBI score, FIB-4 index and APRI score. The optimal value of serum GP73 to predict overall complications and major complications was 80.9 and 79.2 respectively. Serum GP73 levels were independent factors affecting the incidence of overall complications (odds ratio [OR], 3.996; 95% CI 2.152–7.421; P

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0&ndash, A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM &le, 8 kilopascal (kPa) suggested a reduced risk of late recurrence (&gt, 12 months) (hazard ratio (HR), 0.519, 95% confidence interval (CI), 0.307&ndash, 0.877, p = 0.014). Older age at surgery (&ge, 45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270, 95% CI, 1.296&ndash, 8.251, p = 0.012, and HR, 3.146, 95% CI, 1.396&ndash, 7.089, p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251, 95% CI, 0.086&ndash, 0.756, p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (&lt, 1.5) (HR, 0.251, 0.759, p = 0.041). Having early HCC recurrence (HR, 9.416, 95% CI, 3.566&ndash, 24.861, p &lt, 0.001) and microvascular tumor invasion (HR, 3.191, 95% CI, 1.188&ndash, 8.568, p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (&le, 8 kPa) predicted reduced late HCC recurrence.

Purpose The purpose of this study was to evaluate the diagnostic utility of noninvasive Vibration-Controlled Transient Elastography (VCTE) for assessing liver fibrosis in pediatric intestinal failure (PIF) patients. Methods Data from children with severe intestinal failure (≥ 90 days parenteral nutrition dependence) who underwent liver stiffness measurement (LSM), as measured by VCTE, at our institution between December 2015 and March 2018 were reviewed. LSM was compared to METAVIR fibrosis score (F0-F4) on liver biopsy performed within 1 year of VCTE. Results Seventy children underwent 75 LSM. Sixty-three patients (38% female) had at least one valid LSM, and 63% had a history of cholestasis (direct bilirubin ≥ 2 mg/dL). Median (IQR) age at first valid LSM was 4.5 years (2.6, 8.7). Sixteen patients had a liver biopsy. LSM differentiated between METAVIR F0-F1 (n = 6) and F2-F4 (n = 10) with an area under the receiver operating characteristic (AUROC) curve of 0.883 (95% CI: 0.686–0.999). The optimal cut-point derived to predict F2-F4 was an LSM ≥ 6 kPa (sensitivity 80%, specificity 100%). Conclusion LSM as determined by VCTE can distinguish mild (F0-F1) from moderate/severe (F2-F4) liver fibrosis in PIF. VCTE could allow for serial noninvasive monitoring of liver injury, potentially facilitating timely modifications to hepatoprotective management. Type of Study: Study of Diagnostic Test. Level of Evidence: II.

BACKGROUND AND AIMS It is paramount to identify predictors of treatment failure with direct antiviral agents in 'field-practice' patients, including people who inject drugs (PWID). Data on the efficacy of glecaprevir/pibrentasvir (GLE/PIB) in a field-practice scenario are scant. The multicentre MISTRAL study enrolled 1177 patients, including PWID, to assess real-life efficacy and safety of GLE/PIB and to identify the predictive factors for this treatment. METHODS This was a prospective, longitudinal study. The outcome variable was the rate of sustained virological response (SVR) at week 12. RESULTS A total of 123 patients (10%) were infected from hepatitis C virus (HCV) 3. METAVIR fibrosis score was F4 in 104 subjects (9%); 118 patients (10%) were PWID. Overall, 1163/1177 (99%) patients achieved SVR. The baseline clinical factors discriminating between treatment success and treatment failure were age at treatment (P = 0.031) and creatinine level (P = 0.034). SVR rates were not influenced by gender, substance abuse, previous treatment, treatment duration, fibrosis or chronic kidney disease stage. Compared with non-substance users, the 118 PWID exhibited a significantly different genotype pattern distribution (χ2

The launch of new direct-acting antivirals (DAAs) is expected to substantially reduce the burden of hepatitis C virus (HCV) in China. However, the effect of these changes has not yet been modeled in China. Therefore, we aim to predict the burden of HCV-related diseases in China by simulating different scenarios that incorporate recent therapeutic advances of HCV and China's current screening strategy. We developed an individual-based microsimulation Markov model that simulated disease progression of HCV-infected patients in China from 2004 to 2050. We simulated four scenarios with different assumptions about treatment, including a natural history scenario, a pre-DAAs scenario, a DAA treatment for all patients with a METAVIR fibrosis score ≥F3 (DAAs [≥F3]) scenario, and a DAAs (≥F0) scenario. The introduction of DAAs is predicted to have great impacts on the burden of HCV in China, particularly under the DAAs (≥F0) scenario in which we rapidly expand DAAs to all HCV-infected patients (≥F0) in 2021. Under this scenario, prevalence of chronic HCV is expected to peak at 10.75 million (95% confidence interval [CI], 8.30-12.85) around 2020 and then decrease to 7.92 million (95% CI, 5.41-10.08) in 2050. Conclusion: If the future increasing burden of HCV-related diseases is to be averted, China needs to start launching the new DAA treatment and rapidly increase the number of patients treated. However, to maximize the benefits of new DAAs, expanded screening is necessary to identify more cases that require treatment in the short term. Without these changes, the HCV burden in China will remain high in the future.

To assess the diagnostic efficacy of multiparametric MRI using quantitative measurements of the apparent diffusion coefficient (ADC) of the liver parenchyma on diffusion-weighted imaging (DWI), signal intensity (SI) on susceptibility-weighted imaging (SWI), and gadoxetic acid-enhanced T1-weighted imaging during the hepatobiliary phase for the staging of liver fibrosis. Seventy-seven patients underwent a 3T MRI examination, including DWI/SWI sequences and gadoxetic acid-enhanced T1-weighted MRI. Liver fibrosis according to liver biopsy was staged using the Metavir fibrosis score: F0 (n = 21, 27.3 %); F1 (n = 7, 9.1 %); F2 (n = 8, 10.4 %); F3 (n = 12, 15.6 %); and F4 (n = 29, 37.7 %). SI of the liver was defined using region-of-interest measurements to calculate the ADC values, the relative enhancement (RE) in the hepatobiliary phase, and the liver-to-muscle ratio (LMR) measurements for SWI. The values of RE, LMR, and ADC measurements were statistically significantly different among the five fibrosis stages (p

OBJECTIVES The purpose of this study was to evaluate liver fibrosis by acoustic radiation force impulse (ARFI) measurements at 2 locations in patients with chronic hepatitis B and C. METHODS A total of 204 consecutive patients (146 male and 58 female) with chronic hepatitis B (n = 121) and C (n = 83) who underwent liver biopsy were enrolled. All patients received ARFI measurements at 2 locations in the right intercostal space on the same day as biopsy. RESULTS There was no difference in median ARFI values between detection locations. However, a significant difference was found for low and high values between locations (median ± SD, 1.38 ± 0.43 versus 1.56 ± 0.55 m/s; P < .001). By receiver operating characteristic (ROC) curve analysis for a METAVIR fibrosis score of F4 (cirrhosis), the lower value of 2 measurements had the highest area under the ROC curve (0.750), followed by the mean value (0.744) and the higher value (0.730). Patients with hepatitis C had a higher area under the ROC curve than patients with hepatitis B (0.824 versus 0.707) for predicting liver cirrhosis. By logistic regression analysis, ARFI was the best modality for predicting liver cirrhosis in hepatitis C, and conventional sonography was the best modality in hepatitis B (P < .001). The ARFI value in patients with hepatitis B was significantly influenced by liver inflammation (P = .019). CONCLUSIONS Acoustic radiation force impulse imaging is the modality of choice for predicting liver cirrhosis in chronic hepatitis C, whereas conventional sonography is still the modality of choice in chronic hepatitis B.

Food intake increases liver stiffness, but it is believed that liver stiffness returns to baseline two hours after a meal. The aim of this study was to investigate the impact of different sized meals on liver stiffness. Liver and spleen stiffness was measured with transient elastography (TE) and real-time 2-dimensional shear wave elastography (2D-SWE). Patients ingested a 625 kcal and a 1250 kcal liquid meal on two consecutive days. We measured liver and spleen elasticity, Controlled attenuation parameter (CAP) and portal flow at baseline and after 20, 40, 60, 120 and 180 minutes. Sixty patients participated, 83% with alcoholic liver disease. Twenty-eight patients had METAVIR fibrosis score F0-3 and 32 patients had cirrhosis. Liver stiffness, spleen stiffness and CAP increased after both meals for all stages of fibrosis. False positive 2D-SWE liver stiffness measurements caused 36% and 52% of patients with F0-3 fibrosis to be misclassified with higher stages of fibrosis after the moderate and high caloric meal. Likewise, 10% and 13% of compensated cirrhosis patients were misclassified with clinically significant portal hypertension after the two meals. We observed similar misclassification rates with TE. After three hours, liver stiffness remained elevated more than 20% from baseline in up to 50% of patients.IN CONCLUSION: Liver stiffness, spleen stiffness and CAP increase after a meal across all stages of fibrosis and across elastography techniques. Up to half of patients may be misclassified with higher stages of fibrosis, if they are assessed after less than three hours fasting period.

International audience; OBJECTIVE: We hypothesized that, in Human Immunodeficiency Virus and Hepatitis C Virus (HIV/HCV) co-infected patients who did not respond to peg-interferon and ribavirin, a maintenance therapy with peg-interferon could induce fibrosis regression. METHODS: This was a randomized study with two parallel groups. HIV/HCV co-infected patients received peg-interferon α-2a at 180 μg/week or remained on observation for 96 weeks. The primary endpoint was the percentage of patients who experienced a decrease of at least one point in their Metavir fibrosis score between initial and final liver biopsies. Secondary endpoints included plasma fibrosis markers at week 96, occurrence of HCV-related complications, and survival. RESULTS: A total of 52 patients were randomized (peg-interferon: 25; control: 27) including 18 with cirrhosis. The median (interquartile range) age was 44 (40-46) years, and 69% were male. A total of 64% had ALT levels >1.5 normal values, and the CD4 cell count was 391 (296-537) cells/mm(3); 67% of patients had HIV RNA

SUMMARY. There are few data about the long-term histological outcome of HIV-/HCV-coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow-up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow-up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log-rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33– 7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05–1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow-up after SVR to interferon therapy in HIV-/HCV-coinfected patients.

Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel fibrosis marker. We examined the ability of M2BPGi to predict liver fibrosis in patients with biliary atresia. Sixty-four patients who underwent living donor liver transplantation (LDLT) were included [median age, 1.1 years (range 0.4–16.0), male 16 patients (25.0 %)]. We examined M2BPGi levels in serum obtained the day before LDLT, and we compared the value of the preoperative M2BPGi levels with the histological evaluation of fibrosis using the METAVIR fibrosis score. Subsequently, we assessed the ability of M2BPGi levels to predict fibrosis. The median M2BPGi level in patients with BA was 6.02 (range, 0.36–20.0), and 0, 1, 1, 11, and 51 patients had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F4 fibrosis, the median M2BPGi level was 6.88 (quartile; 5.235, 12.10), significantly higher than that in patients with F3 fibrosis who had a median level of 2.42 (quartile; 1.93, 2.895, p

Interleukin 33 (IL-33) is a cytokine belonging to the IL-1 superfamily. Soluble ST2 (sST2) binds to IL-33 and by functioning as trap receptor inhibits signal sending to Th2 via transmembrane ST2. Because Th2-type cytokines play an important role in fibrosis, the aim of this study is to determine whether sST2 can be used as a marker of fibrosis in chronic hepatitis B (CHB) patients or not. The study included 19 healthy controls, 54 patients with CHB, and 14 patients with cirrhosis because of CHB. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4) scores also calculated, and correlations between liver biopsies, sST2 levels, and these scores were analyzed in CHB and cirrhosis patients. The sST2 levels in patients with CHB were significantly higher than those in the control group subjects (median: 1133 pg/mL vs 762.5 pg/mL, respectively [P = 0.035]). In CHB patients, the METAVIR fibrosis score (stages from 0 to 4) showed a moderate correlation with serum sST2 level (r = 0.396, P = 0.004) and a weak correlation with FIB-4 score (r = 0.359, P = 0.008), but no correlation with APRI score (r = 0.253, P = 0.06). The under the curve value of serum sST2 was 0.68, and its prediction of significant fibrosis (METAVIR score ≥2) in values >674 pg/mL had a sensitivity of 91.7% and specificity of 40% (P = 0.009). According to multiple logistic regression analysis, only METAVIR fibrosis stage was found to be an independent predictor of serum sST2 elevation in CHB patients (P = 0.04). The sST2 level can be used for differentiating significant fibrosis from mild fibrosis in CHB patients. However, the efficacy of this marker should be verified by larger studies in the future.

We evaluated whether quantitative measurements of liver fibrosis with recently developed diagnostics outperform histological staging in detecting natural or interferon-induced changes. We compared Metavir staging, morphometry (area and fractal dimension) and six blood tests in 157 patients with chronic hepatitis C from two trials testing maintenance interferon for 96 weeks. Paired liver biopsies and blood tests were available for 101 patients, and there was a significant improvement in Metavir activity and a significant increase in blood tests reflecting fibrosis quantity in patients treated with interferon when compared with controls - all per cent changes in histological fibrosis measures were significantly increased in F1 vs F2-4 stages only in the interferon group. For the whole population studied between weeks 0 and 96, there was significant progression only in the area of fibrosis (AOF) (P = 0.026), FibroMeter (P = 0.020) and CirrhoMeter (P = 0.003). With regards to dynamic reproducibility, agreement was good (r(ic) ≥ 0.72) only for Metavir fibrosis score, FibroMeter and CirrhoMeter. The per cent change in AOF was significantly higher than that of fractal dimension (P = 0.003) or Metavir fibrosis score (P = 0.015). CirrhoMeter was the only blood test with a change significantly higher than that of AOF (P = 0.039). AOF and two blood tests, reflecting fibrosis quantity, have high sensitivity and/or reproducibility permitting the detection of a small progression in liver fibrosis over two years. A blood test reflecting fibrosis quantity is more sensitive and reproducible than morphometry. The study also shows that maintenance interferon does not improve fibrosis, whatever its stage.

Background: Although liver biopsy (LB) is the gold standard for the morphological diagnosis of diseases of the liver, recent noninvasive tests may also help in the evaluation of liver fibrosis. We have studied blood fibrosis markers and liver stiffness (LS) measurement to assess fibrosis in different forms of chronic hepatitis C virus (HCV) infection. Patients and methods: Out of 119 HCV-infected patients, 75 had biopsy-proven chronic hepatitis C, 24 had HCV cirrhosis, 20 individuals were symptom-free HCV carriers with persistently normal alanine aminotransferase (PNA), and 30 healthy blood donors served as controls. Wai's aspartate-aminotransferase (AST) to platelet ratio index (APRI) was calculated from serum AST and blood platelet number. Serum HCV-RNA (hepatitis C virus ribonucleic acid), procollagen-III-peptide (P-III-P) and hyaluronic acid (HA), plasma transforming growth factor β-1 (TGFβ-1), Knodell's histological activity index (HAI), and METAVIR fibrosis score were determined, and for LS...

Background & Aims The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR⩾F2) in patients with chronic viral hepatitis. Methods A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. Results The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77–0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72–0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0–60% of patients (cirrhosis) and 9–30% of patients (significant fibrosis). Conclusions The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.

Background The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. Aim The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. Method Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. Results There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. Conclusion Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.

BACKGROUND/AIMS Several simple tests for hepatic fibrosis employ indirect markers. However, the efficacy of using direct and indirect serum markers to predict significant fibrosis in clinical practice is inconclusive. We analyzed the efficacy of a previously reported indirect marker of hepatic fibrosis - the aspartate aminotransferase to platelet ratio index (APRI) - in patients with nonalcoholic chronic liver diseases (CLDs). METHODS A total of 134 patients who underwent a percutaneous liver biopsy with a final diagnosis of chronic hepatitis B (n=93), chronic hepatitis C (n=18), or nonalcoholic fatty liver disease (n=23) were enrolled. A single-blinded pathologist staged fibrosis from F0 to F4 according to the METAVIR system, with significant hepatic fibrosis defined as a METAVIR fibrosis score of >/=2. RESULTS The mean area under the receiver operating characteristic curve (AUROC) of APRI for predicting significant fibrosis in nonalcoholic CLDs was 0.84 [95% confidence interval (CI), 0.78-0.91]. APRI yielded the highest mean AUROC in the patients with chronic hepatitis B (0.85; 95% CI, 0.771-0.926). The positive predictive value of APRI >/=1.5 for predicting significant fibrosis was 89%. The negative predictive value of APRI

Objective: The aim of this study was to determine the test characteristics of direct and indirect biomarkers for liver fibrosis compared with transient elastography (TE) among a group of human immunodeficiency virus (HIV)-infected and uninfected women with or without Hepatitis C virus (HCV) infection. Methods: Women enrolled in the Women’s Interagency HIV Study (WIHS) from Washington DC, San Francisco, and Chicago with a body mass index (BMI)

Purpose. To noninvasively assess liver fibrosis using combined-contrast-enhanced (CCE) magnetic resonance imaging (MRI) and texture analysis.Materials and Methods. In this IRB-approved, HIPAA-compliant prospective study, 46 adults with newly diagnosed HCV infection and recent liver biopsy underwent CCE liver MRI following intravenous administration of superparamagnetic iron oxides (ferumoxides) and gadolinium DTPA (gadopentetate dimeglumine). The image texture of the liver was quantified in regions-of-interest by calculating 165 texture features. Liver biopsy specimens were stained with Masson trichrome and assessed qualitatively (METAVIR fibrosis score) and quantitatively (% collagen stained area). UsingL1regularization path algorithm, two texture-based multivariate linear models were constructed, one for quantitative and the other for quantitative histology prediction. The prediction performance of each model was assessed using receiver operating characteristics (ROC) and correlation analyses.Results. The texture-based predicted fibrosis score significantly correlated with qualitative (r=0.698,P<0.001) and quantitative (r=0.757,P<0.001) histology. The prediction model for qualitative histology had 0.814–0.976 areas under the curve (AUC), 0.659–1.000 sensitivity, 0.778–0.930 specificity, and 0.674–0.935 accuracy, depending on the binary classification threshold. The prediction model for quantitative histology had 0.742–0.950 AUC, 0.688–1.000 sensitivity, 0.679–0.857 specificity, and 0.696–0.848 accuracy, depending on the binary classification threshold.Conclusion. CCE MRI and texture analysis may permit noninvasive assessment of liver fibrosis.

Objective: To evaluate the prevalence and severity of steatosis and possible interactions between steatosis, host factors, viral factors, and treatment for HIV infection in HIV-hepatitis C virus (HCV) coinfected patients. Methods: Steatosis was assessed among 395 HIV-HCV coinfected patients who were enrolled in the ANRS trial HC02 Ribavic and for whom histological data were available. Steatosis was graded as follows: 0 (none); 1 ( 70%). Results: Steatosis was present in 241 patients (61%), of whom 149 (38%) had grade 1, 64 (16%) grade 2 and 28 (7%) grade 3. In multivariate analysis, the following five independent risk factors were associated with steatosis: HCV genotype 3 [odds ratio (OR), 3.02; 95% confidence interval (Cl), 1.91-4.79; P < 0.0001], the mean METAVIR fibrosis score (OR, 1.43; 95% Cl, 1.11 -1.84; P = 0.0053), the body mass index (BMI; OR, 1.13; 95% Cl, 1.05-1.21; P = 0.0013), HCV viral load (OR. 1.65; 95% Cl, 1.22-2.23; P= 0.0012) and ferritin (OR, 1.13; 95% Cl, 1.06-1.21; P < 0.0003). As HCV genotype 3 was a risk factor for steatosis, further exploratory analyses were stratified according to the HCV genotype (1 and 3). Factors independently associated with steatosis were BMI and HCV viral load in patients with HCV genotype 3 infection and the mean METAVIR fibrosis score, the BMI and ferritin in patients with HCV genotype 1 infection. Conclusion: Steatosis is particularly frequent in HIV-HCV coinfected patients, who appear to have the same risk factors for steatosis as HCV monoinfected patients. None of the characteristics of HIV infection, including antiretroviral therapy, was independently associated with steatosis.

Liver fibrosis plays a pivotal role in liver function impairment and is a feature of chronic infection by hepatitis C virus (HCV). Ten to 20% of patients progress to cirrhosis leading to an increased risk of liver failure or hepatocellular carcinoma (HCC). Recent advances have culminated in clear evidence that fibrosis can be reversible, and in expectation that effective anti-fibrotic therapy will improve the prognosis. Among the different cellular pathways involved in fibrosis, the transforming growth factor-β1 (TGF-β1) signaling plays a major role. Increases of TGF-β1 expression is associated with fibrotic diseases and this cytokine could be a target for an antifibrotic drug. Clinical results on radiation-induced fibrosis have brought some evidences that Cu–Zn SOD (SOD1) could be an anti-fibrotic drug. Its therapeutic effect could be related to a down-regulation of TGF-β1 as proved in a well characterized pig model of radiation induced fibrosis, where the efficacy of Cu–Zn SOD has been shown in reversing fibrosis. Using 3-D skin co-culture of fibroblasts from this pig model, it was showed that SOD significantly reduces the expression of the TGFβ1, both at the mRNA and protein level. An experimental work could be undertaken to validate the Cu–Zn SOD as an anti-fibrotic drug, using HCV core protein expressing transgenic mice. As the current anti-HCV therapy with pegylated interferon combined with ribavirin can eradicate virus and stop the progression of fibrosis, but near 50% of HCV infected patients are non responders, a controlled trial is planned for HCV infected patients non responders to this therapy with a Metavir fibrosis score reaching F = 2 or > 2.

BACKGROUND: Studies of viral hepatitis C have suggested that fibrosis can regress, at least in patients with sustained virological response. A recent study suggested that cirrhosis was reversible in sustained and non-virological responders. AIM: To study fibrosis progression rate and cirrhosis reversion in patients treated for severe fibrosis with interferon or interferon + ribavirin. PATIENTS AND METHODS: Ninety-nine patients were treated with interferon + ribavirin and 64 with interferon. The Metavir fibrosis score and the semiquantitative fibrosis score (SFS) were used to assess fibrosis. RESULTS: In sustained responders, fibrosis progression rate decreased from 0.26 Metavir unit (interquartile range: 0.19-0.34) to -0.67 (-0.67 to 0) (P < 0.0001) and from 0.81 SFS unit (0.48-1.13) to -1.33 (-3.67 to 0) (P < 0.0001). In non-responders, fibrosis progression rate decreased from 0.25 Metavir unit (0.17-0.33) before treatment to 0 (0-0) during treatment (P = 0.002) and from 0.63 SFS unit (0.49-1.12) to 0 (-2.67-1.33) (P = 0.18). Six out of 18 (33%) sustained virological responders and four of 43 (9%) non-responders regressed from cirrhosis (F4) to severe fibrosis (F3) (P = 0.058). No patient with cirrhosis had a decrease of Metavir fibrosis score of 2 points. CONCLUSION: Interferon can slow fibrosis progression in sustained virological responders with severe fibrosis. In patients with a non-virological response and treated for 12 months the fibrosis progression rate was nil, meaning that only fibrosis stabilization could be obtained in these patients. Then, longer treatment duration (3-4 years) could be evaluated in non-virological responders.

Information on the stage of liver fibrosis is essential in managing chronic hepatitis C (CHC) patients. However, most models for predicting liver fibrosis are complicated and separate formulas are needed to predict significant fibrosis and cirrhosis. The aim of our study was to construct one simple model consisting of routine laboratory data to predict both significant fibrosis and cirrhosis among patients with CHC. Consecutive treatment-naive CHC patients who underwent liver biopsy over a 25-month period were divided into 2 sequential cohorts: training set (n = 192) and validation set (n = 78). The best model for predicting both significant fibrosis (Ishak score > or = 3) and cirrhosis in the training set included platelets, aspartate aminotransferase (AST), and alkaline phosphatase with an area under ROC curves (AUC) of 0.82 and 0.92, respectively. A novel index, AST to platelet ratio index (APRI), was developed to amplify the opposing effects of liver fibrosis on AST and platelet count. The AUC of APRI for predicting significant fibrosis and cirrhosis were 0.80 and 0.89, respectively, in the training set. Using optimized cut-off values, significant fibrosis could be predicted accurately in 51% and cirrhosis in 81% of patients. The AUC of APRI for predicting significant fibrosis and cirrhosis in the validation set were 0.88 and 0.94, respectively. In conclusion, our study showed that a simple index using readily available laboratory results can identify CHC patients with significant fibrosis and cirrhosis with a high degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among CHC patients.

In alcoholic liver disease, fibrosis classically begins around the centrilobular veins, while portal tract fibrosis is described as inconstant and septal fibrosis is a late event. The aim of this study was to compare the roles of centrilobular fibrosis (CLF) and portal tract/septal fibrosis (PTF) especially in alcoholic chronic liver disease. One hundred and sixty patients with alcoholic chronic liver disease and 83 controls with viral chronic hepatitis were included. The PTF score, derived from the Metavir score, CLF and the area of fibrosis, assessed by image analysis, were evaluated on liver biopsies in addition to blood markers of fibrosis. The correlation between the PTF score and the area of fibrosis was higher in alcoholic liver disease (r = 0.87, p < 10(-4)) than in viral chronic hepatitis (r = 0.66, p < 10(-4)). The PTF score correlated with the CLF score (r = 0.92, p < 10(-4)), serum hyaluronate (r = 0.76, p < 10(-4)), and the prothrombin index (r = -0.77, p < 10(-4)). Multiple regression analyses showed that the area of fibrosis was explained only by the PTF score and not by the CLF score. PTF appears more frequent than CLF in alcoholic chronic liver disease, suggesting that PTF may precede CLF. PTF is more responsible for the amount of fibrosis than CLF. The results of this study also validate the use of the Metavir fibrosis score in alcoholic chronic liver disease.

Steatosis is observed in around 25 to 70% of HIV-infected subjects. Steatosis is multifactorial. Steatosis was mainly related to denutrition and opportunistic infections at the Aids era then to nucleosidic analogues and mitochondrial cytopathies. Today, it is mainly associated with HAART- related lipodystrophy, and other classical causes (hyperlipidemia, diabetes, HCV infection) leading to insulin resistance. In the ANRS HC 02 RIBAVIC trial, in 395 co-infected HIV-HCV patients, steatosis was observed in 241 patients (61%). Among them, 38% had a grade I steatosis (less than 30% of fatty hepatocytes), 16% had a grade II steatosis (30 to 70% of hepatocytes) et 7% a grade III (more than 70% of hepatocytes). In multivariate analysis, factors independently associated with steatosis were genotype 3, Metavir fibrosis score, body mass index, HCV viral load and ferritinemia. Lipodystrophy and antiretroviral treatment were rarely associated with steatosis in the ANRS HC 02 RIBAVIC and APRICOT trials. In these trials, steatosis worsened the fibrosis progression but did not impact on the rate of sustained virological response. Finally, steatosis significantly decreases in patients with sustained virological response.

Interferon alpha-2b (IFN-α 2b) was the first drug approved for the treatment of hepatitis C virus (HCV) in Europe and North America. Since 1986 IFN-α2b has been evaluated thoroughly and confirmed as the basic treatment for hepatitis C. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy to risk ratio seems to favor 3 million units (MU) of interferon (IFN) administered three times a week for 12 months. In the first meta-analysis of trials using this regimen, a sustained alanine aminotransferase (ALT) response was seen in nearly 35% of patients, and a histologic improvement was observed in 56%. 34 The results of the two most recent randomized trials of IFN therapy, 3 MU three times a week for 48 weeks, 25,35 in 503 treatment-naive patients, have been evaluated using a centralized serum ALT assessment, sensitive assay of viral load (100 copies/mL), and Knodell and METAVIR histologic scoring systems. In these trials, 22% of patients had a sustained ALT response 24 weeks after the end of treatment, 16% had a sustained HCV RNA response, 50% showed an improvement in Knodell score, 36% had an improved METAVIR score, and 18% had an improved METAVIR fibrosis score. Because of these discrepancies, re-treatment with IFN therapy is being considered in patients who have not responded with prolonged viral eradication. 39 The usefulness of IFN treatment in these patients may be related to a partial antiviral effect, to an antifibrotic effect, and to an anticarcinogenic effect. 5,22,29,31 According to recent results of randomized trials comparing ribavirin and IFN combination therapy, there probably is no longer a place for IFN monotherapy as a first-line treatment. 23,25 There will still be a place for IFN monotherapy, however, for the 60% of patients who do not have a sustained virologic response to combination therapy if IFN alone can reduce the progression to cirrhosis or the incidence of complications of cirrhosis, including hepatocellular carcinoma. This article analyzes the effect of IFN therapy on the course of disease in HCV-infected patients, using the endpoints of viral load, serum ALT activity, histologic activity, fibrosis, and the development of or death from hepatocellular carcinoma.

Background Liver biopsy has been the reference standard when evaluating fibrosis due to recurrent hepatitis after liver transplantation. Magnetic resonance elastography estimates liver stiffness, correlating to fibrosis. Aim To investigate the utility of elastography in staging liver fibrosis in transplant recipients with hepatitis C. Methods Fifty-four patients, ≥12 months post-transplant, underwent elastography within three months of biopsy. Discriminatory capability for METAVIR fibrosis stages F0–2 vs. F3–4 and receiver operating characteristic curve (ROC) analysis were determined. Results On biopsy, 27 patients had METAVIR fibrosis score 0–1; 12 had a 3 or 4. There was significant correlation between histologic fibrosis and shear stiffness (R² = 0.588, p

The objective of our study was to describe the cross-sectional imaging appearance of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection in the absence of advanced fibrosis and cirrhosis.This study is a retrospective review of our surgical database to identify patients with chronic HCV infection and HCC who underwent hepatectomy and who had undergone preoperative CT or MRI. Only patients with a Metavir fibrosis score of F0, F1, or F2 on pathology were included. Patients with hepatitis B virus coinfection or other causes of chronic liver disease and patients with histopathologic evidence of advanced fibrosis or cirrhosis (Metavir scores F3 and F4) were excluded. Contrast-enhanced CT or MRI examinations performed within 2 months before surgery were reviewed for the number, size, and location of tumors; tumor enhancement characteristics; and presence of macrovascular invasion.Two hundred forty-five resections of HCC in patients with HCV were performed in our institution from 1987 to 2012. Of this group, 26 patients (10.6%) had a Metavir fibrosis score of F0, F1, or F2; of those patients, 19 (18 men and one woman; 18 non-Asian patients and one Asian patient; mean age, 64 years) had imaging studies available for review. Twenty-one HCCs (mean size, 4.5 cm; range, 0.9-14.8 cm) were evaluated at imaging. Typical wash-in and washout characteristics were seen in 16 of 19 viable lesions (84.2%). The remaining two HCCs were completely necrotic after transarterial chemoembolization. Eighteen patients had a solitary tumor. Most tumors (15/21, 71.4%) developed in the right hepatic lobe.HCC can develop in patients with chronic HCV without advanced fibrosis or cirrhosis, most frequently in older non-Asian men, and usually appears as a large solitary tumor with a typical wash-in-washout enhancement pattern.

Lymphocytes play an active role in natural immunity against hepatitis C virus (HCV). We hypothesized that a lower absolute lymphocyte count (ALC) may alter HCV outcome after liver transplantation (LT). The aim of this study was to investigate the impact of peritransplant ALC on HCV recurrence following LT. A total of 289 LT patients between 2005 and 2011 were evaluated. Peritransplant ALC (pre-LT, 2-week, and 1-month post-LT) and immunosuppression were analyzed along with recipient and donor factors in order to determine risk factors for HCV recurrence based on METAVIR fibrosis score. When stratifying patients according to pre- and post-LT ALC ( 1,000/μL), lymphopenia was significantly associated with higher rates of HCV recurrence with fibrosis (F2-4). Multivariate Cox regression analysis showed posttransplant ALC at 1 month remained an independent predictive factor for recurrence (P = 0.02, hazard ratio [HR] = 2.47 for

Background & Aims Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC 3 included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. Methods Patients with F2/F3 MFS who failed retreatment were randomized to PegIFNα-2b (0.5μg/kg/week, n=270) or observation (n=270) for 36months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest. Results In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PegIFNα-2b and 11% of observation patients had improvement in MFS ( p =0.32). More PegIFNα-2b than observation patients had improvement in activity score (20% vs. 9%; p 0.001). Among patients treated for >2.5years, improvement in MFS or activity score was more common with PegIFNα-2b than observation (21% vs. 14%, p =0.08 and 26% vs. 10%, p 0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PegIFNα-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PegIFNα-2b was similar to previous studies. Conclusions PegIFNα-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5years. Both FibroTest and ActiTest were significantly improved during maintenance therapy.

Histological activity reflects the global assessment of basic necroinflammatory lesions and is a criterion of major importance in chronic hepatitis C. The aim of this study was to propose and test the accuracy of a simple algorithm that generates a single activity score based on basic pathological features. A panel of 10 pathologists reviewed 363 chronic hepatitis C liver biopsies and graded the activity of hepatitis according to their own experience (reference activity). Then, a consensual algorithm on the grading of activity was established by the 10 experts in a panel discussion. Finally, stepwise discriminant analysis was performed to define which basic features had been intuitively used in the reference activity (statistical activity). To test the accuracy of the algorithm, concordance between the activity defined by the algorithm and the reference activity was assessed. It was compared with concordance between the activity defined by the statistical model and the reference activity. The algorithm proposed by the panel for the grading of activity included piecemeal necrosis and lobular necrosis. Concordance between reference activity and activity defined by the algorithm was substantial (305 cases, 84%, kappa = .75). Discriminant analysis showed that piecemeal necrosis, lobular necrosis, and portal inflammation were independently used to grade the activity. Concordance between reference activity and activity defined by the statistical model was substantial (300 cases, 83%, kappa = .73), virtually identical to the concordance between reference activity and activity defined by algorithm. This study proposes a simple algorithm for the grading of activity in chronic hepatitis. Its accuracy is as high as that obtained using a statistical approach.

Quantification of liver fibrosis by non invasive means is a major challenge that has stimulated the search for new approaches. The prognosis and clinical management of chronic liver diseases are highly dependent on the extent of liver fibro¬sis, as complications mainly occur in patients in the advanced stages. This is particularly true in patients with chronic hepatitis C (HCV). Liver biopsy with METAVIR analysis is the gold standard for assessing liver fibrosis associated with HCV [1-3]. It is an invasive and expensive procedure that is not well accepted by many patients especially when repeated exam¬inations are needed. Moreover, its accuracy in assessing fibrosis is questionable, as reproducibility is poor due to sampling errors, and even in adequately sized spec¬imens, intra-observer and inter-observer discrepancies are seen [4-7]. Our research shows that a special type of blood test which we have developed, the ‘Fibrogenic Stimulation Index’ (FSI), can identify patients with liver fibrosis. The FSI assesses the stimulation of proliferation of fibroblasts and hepatic stellate cells (HSCs), the key cell involved in hepatic fibrosis, in response to patients’ sera samples. The FSI is a cell based assay of fibrosis that assesses the ability of patients’ sera samples to stimulate proliferation of selected target cells. The type of fibrosis to be assessed is matched with a specific target cell. The FSI is a noninvasive test which uses patients’ sera samples in an in vitro assay which can detect and quantify the degree of fibrosis based on a patient’s blood sample. Our data suggests that FSI correlates with procollagen type III peptide (P-III-P) another measure of hepatic fibrosis and that both the FSI and P-III-P correlate with METAVIR fibrosis score. Further study in the larger cohort of HCV patients indicates that FSI is a positive predictor of fibrosis in HCV patients. We were the first to reported on the role for platelet derived growth factor (PDGF) in experimental models of hepatic fibrosis [8,9] and we showed that PTX blocked fibrosis via an effect on PDGF and that this occurred by blocking phosphorylation of c-jun on serine 73 [10]. We began investigations of non alcoholic steatohepatitis (NASH) mediated fibrosis [11,12] and reported that ribavirin but not interferon inhibited fibrosis also associated with HCV and that this effect was mediated by the block of phosphorylation of c-jun on ser 73 and resulted in decreased synthesis of collagen and hepatic stellate cell (HSC) proliferation [13]. We reported that PTX decreased NASH sera-stimulated FSI (our patented diagnostic test for fibrosis using HSCs as the target cell) and c-Jun phosphorylation as assessed by 3H-thymidine incorporation and Western analysis respectively, such that NASH patient sera stimulated HSC proliferation and increased phosphorylated c-Jun in HSCs and that PTX significantly decreased NASH patient sera stimulated HSC proliferation and decreased NASH sera-stimulated phosphorylated c-Jun in HSCs [14]. Our recent published [15] and unpublished data indicate that PTX decreased the FSI; that the FSI correlates well with the METAVIR fibrosis score in HCV patients and may be predictive of fibrosis in this cohort; this intellectual property is patented [16]. Pancreatic fibrosis shows remarkable though not surprising similarities to hepatic fibrosis. From the Binkley and colleagues early studies on molecular basis of pancreatic fibrosis [17] to the more recent studies of Krantz and colleagues on the molecular understanding of the role of TGFβ in this disorder [18]; the diseases run in parallel. It would be exciting to work more closely with those who are making such great advances in the area of pancreatic fibrosis and facilitate the development of novel therapeutics that could potentially cure both. References

Background: IL-33 is a novel member of the IL-1 family, which has been shown to play an important role in T helper 2 (Th2)-associated immune responses. Recent studies have suggested a possible role for IL-33 in the pathogenesis of liver damage during acute and chronic hepatitis; furthermore, IL-33 may be involved in the development and progression of liver fibrosis. Objectives: To evaluate serum IL-33 levels in a group of patients with chronic hepatitis C (CHC) genotype 1b at enrolment and after a course of pegylated (PEG)-IFN plus ribavirin. Patients and Methods: 60 patients with chronic hepatitis C (CHC) and 65 healthy controls were examined and compared for serum IL-33 levels by ELISA. All CHC patients were submitted to liver biopsy either before starting antiviral treatment or during post-treatment follow up. We evaluated whether post-treatment IL-33 concentration was associated with histologic outcome as well as with virologic response to therapy. Results: Serum IL-33 levels were significantly higher among CHC patients in comparison with healthy controls. IL-33 concentration was lower among patients with a METAVIR fibrosis score F1-F2, compared with those having a more advanced liver disease (METAVIR stage F3-F4). In addition, sustained virologic response (SVR) was associated with a significant drop in IL-33 levels, whereas no changes were found among relapsers and nonresponders. Analogously, patients experiencing liver histologic improvement after antiviral therapy had lower posttreatment IL-33 levels in comparison with baseline values. Contrarily, no variations were detected among subjects with worsened or stable histologic features. Conclusions: IL-33 may represent a new and easy-to-detect biomarker for the diagnosis of liver damage in CHC patients, as it appears to be modulated in parallel with biochemical and histologic parameters, such as ALT levels and liver fibrosis. Furthermore, considering that serum IL-33 concentration was significantly reduced following a successful course of antiviral treatment, this cytokine may also represent a sensitive indicator of SVR.

Liver biopsy is used as the “gold standard” for the assessment of the stage and degree of activity in chronic hepatitis C and is of major importance in evaluating the effects of treatment. Because numerous therapeutic trials are undertaken with histological control, the reproducibility of liver biopsy interpretation appears essential. Therefore the aim of this study was to estimate intraobserver and interobserver variations in the assessment of features, classification, and numerical scoring of chronic viral hepatitis C among 10 pathologists specializing in liver diseases. These pathologists independently reviewed 30 liver biopsy specimens of viral hepatitis C and completed a histological form for each of the specimens. Five pairs of pathologists then were randomly designated. They independently reviewed the biopsy specimens and filled out a new coding form. The interobserver variation was calculated for each item among the 10 individuals and then among the five pairs with the intraclass correlation coefficient or ϰ statistics. Five features showed an almost perfect or a substantial degree of concordance among the 10 observers (i.e., cirrhosis, fibrosis, fibrosis grading of Knodell index, steatosis, portal lymphoid aggregates). The 17 other indicators showed a weaker concordance with, for instance, a moderate degree of concordance for piecemeal necrosis, disease activity, Knodell index, a fair degree of concordance for lobular necrosis, and only a slight degree of concordance for six items. Five items had a higher concordance when viewed by a pair of pathologists than when studied by only one pathologist (i.e., steatosis, periportal necrosis grading of Knodell index, lobular necrosis grading of Knodell index, centrilobular fibrosis, and ductular proliferation). Two showed a significant decrease, and the others were unchanged. This study reveals that certain features of major importance in assessing disease activity show significant observer variation. The acceptable degree of concordance of the Knodell index was related mainly to the substantial degree of concordance of the fibrosis score, whereas other numerical items displayed substantial observer variations. Simultaneous observation by two pathologists increased the reproducibility of numerical scoring and of certain viral hepatitis C lesions. A classification of chronic hepatitis C based on dissociated semiquantitative assessment of necroinflammatory lesions and fibrosis offered more reproducibility than the use of a global numerical index. (Hepatology 1994;20:15–20.)

Ishak (modified Knodell score) and METAVIR scores are the most widely accepted scoring systems for assessment of fibrosis and necroinflammation in dealing with chronic hepatitis C. In METAVIR, only interface hepatitis and lobular necrosis determine the grade of activity, while in Ishak, portal infiltrate and confluent necrosis are included with the two previous parameters. Confluent necrosis is very rare in chronic hepatitis C, that in most patients the actual score limit is 12 instead of 18 (Ishak score), that mostly underscore the actual necroinflammation. Also, portal inflammatory infiltrate may reflect immunological response rather than necroinflammation. This may explain the discrepancy between enzyme elevation and necroinflammatory score as determined by Ishak score (modified HAI) in assessment of chronic hepatitis C biopsy specimens. On the other hand, no study has clearly tested such discrepancy in applying METAVIR. Some of the terminologies applied in METAVIR are in need of revision or declaration. For example; the term “septa” is used to mean actual fibrous bridges, while in Ishak score both terms; septa and bridges; are applied by different meaning. Ishak et al, 1995, in their system, applied both terminologies (septa & bridges), however in completely different meaning. Septa, means expansion of portal tract edges without formation of bridges or actual connection between portal areas or portal area and central vein (1). On the other hand, the term bridge was applied to actual fibrous connection between two portal areas or portal area and central vein. Because of this confusion, some studies comparing both scoring systems have committed some mistakes. Some studies have compared both Ishak and METAVIR systems, but they included small number of patients or included hepatitis B and hepatitis C. Therefore, the objectives of this chapter are:  Revision of histological grading and staging in chronic hepatitis C.  Clarification of the METAVIR terminology for future applications.  Establishing an Ishak to METAVIR fibrosis score conversion table.