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This study aimed to evaluate the ability of single nucleotide polymorphisms (SNPs) to refine hepatocellular carcinoma (HCC) risk stratification.Six SNPs in PNPLA3, TM6SF2, HSD17B13, APOE, and MBOAT7 affecting lipid turnover and one variant involved in the Wnt-β-catenin pathway (WNT3A-WNT9A rs708113) were assessed in patients with alcohol-related and/or HCV-cured cirrhosis included in HCC surveillance programs (prospective CirVir and CIRRAL cohorts). Their prognostic value for HCC occurrence was assessed using Fine-Gray models combined into a 7-SNP genetic risk score (GRS). Prediction ability of two clinical scores (a routine nongenetic model determined by multivariate analysis and the external aMAP score) without then with the addition of the GRS was evaluated by C-indices. The standardized net benefit was derived from decision curves.Among 1145 patients, 86 (7.5%) developed HCC after 43.7 months. PNPLA3 and WNT3A-WNT9A variants were independently associated with HCC occurrence. The GRS stratified the population into 3 groups with progressively increased 5-yr HCC incidence [Group 1 (n=627, 5.4%), Group 2 (n=276, 10.7%), and Group 3 (n=242, 15.3%); P0.001]. The multivariate model identified age, male sex, diabetes, platelet count, GGT levels, albuminemia and the GRS as independent risk factors. The clinical model performance for 5-yr HCC prediction was similar to that of the aMAP score (C-Index 0.769). The addition of the GRS to both scores modestly improved their performance (C-Index 0.786 and 0.783, respectively). This finding was confirmed by decision curve analyses showing only fair clinical net benefit.Patients with cirrhosis can be stratified into HCC risk classes by variants affecting lipid turnover and Wnt-β-catenin pathway. The incorporation of this genetic information modestly improves the performance of clinical scores.The identification of patients at higher probability of developing liver cancer is pivotal to improve the performance of surveillance. Risk assessment can be achieved by combining several clinical and biological parameters used in routine practice. The addition of patients' genetic characteristics can modestly improve this prediction and will ultimately pave the way for precision medicine in patients eligible for HCC surveillance, allowing physicians to trigger personalized screening strategies.

Background & Aims In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated. Methods This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: i) Definite or probable AIH based on the simplified IAIHG score; ii) international normalized ratio (INR) ≥1.5 and/or bilirubin >200 μmol/L; iii) No previous history of AIH; iv) Histologically proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3 = (D3–D0)/D0. Results A total of 128 patients were included, with a median age of 52 (39–62) years; 72% were female. Overall survival reached 88%. One hundred and fifteen (90%) patients received corticosteroids, with a LT-free survival rate of 66% at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95% CI 2.23–21.06; p Conclusion In patients with AS-AIH, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort. Lay summary The management of patients with acute severe autoimmune hepatitis is highly challenging, particularly regarding their early referral for liver transplantation. We found that international normalized ratio at the initiation of corticosteroid therapy and the evolution of international normalized ratio and bilirubin values after 3 days of therapy were highly predictive of liver transplantation or death. We are thus proposing a score that combines these variables and identifies patients in whom liver transplantation is urgently required.

Background & Aims: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. Methods: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. Results: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. Conclusions: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. Impact and implications: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved

Background & Aims: Baveno VI and expanded Baveno VI criteria can avoid the need for esophagogastroduodenoscopy (EGD) to screen for varices needing treatment (VNT) in a substantial proportion of compensated patients with viral and/or alcoholic cirrhosis. This multicenter, cross-sectional study aims to validate these criteria in patients with compensated cirrhosis due to non-alcoholic fatty liver disease (NAFLD), accounting for possible differences in liver stiffness measurement (LSM) values between M and XL probes. Methods: We assessed 790 patients with NAFLD-related compensated cirrhosis who had EGD within six months of a reliable LSM, measured by FibroScan® using M and/or XL probe. Baveno VI and expanded Baveno VI criteria were tested. The main variable used to optimize criteria was the percentage of endoscopies spared, keeping the risk of missing large VNT below a 5% threshold. Results: LSM was measured by both M and XL probes (training set) in 314 patients, while only M or XL probe (validation sets) were used to measure LSM in 338 and 138 patients, respectively. In the training set, use of Baveno VI and expanded Baveno VI criteria reduced the number of EGD by 33.3% and by 58%, with 0.9% and 3.8% of large esophageal varices missed, respectively. The best thresholds to rule-out VNT were identified as platelet count >110,000/mm3 and LSM 110,000/mm3 and LSM

Background & Aims Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. Methods This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. Results Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90–96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93–100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). Conclusions Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.

Background & Aims: Controlled attenuation parameter (CAP) is a novel non-invasive measure of hepatic steatosis, but it has not been evaluated in alcoholic liver disease. Therefore, we aimed to validate CAP for the assessment of biopsy-verified alcoholic steatosis and to study the effect of alcohol detoxification on CAP. Methods: This was a cross-sectional biopsy-controlled diagnostic study in four European liver centres. Consecutive alcohol-overusing patients underwent concomitant CAP, regular ultrasound, and liver biopsy. In addition, we measured CAP before and after admission for detoxification in a separate single-centre cohort. Results: A total of 562 patients were included in the study: 269 patients in the diagnostic cohort with steatosis scores S0, S1, S2, and S3 = 77 (28%), 94 (35%), 64 (24%), and 34 (13%), respectively. CAP diagnosed any steatosis and moderate steatosis with fair accuracy (area under the receiver operating characteristic curve [AUC] ≥S1 = 0.77; 0.71–0.83 and AUC ≥S2 = 0.78; 0.72–0.83), and severe steatosis with good accuracy (AUC S3 = 0.82; 0.75–0.88). CAP was superior to bright liver echo pattern by regular ultrasound. CAP above 290 dB/m ruled in any steatosis with 88% specificity and 92% positive predictive value, while CAP below 220 dB/m ruled out steatosis with 90% sensitivity, but 62% negative predictive value. In the 293 patients who were admitted 6.3 days (interquartile range 4–6) for detoxification, CAP decreased by 32 ± 47 dB/m (p 2 had a significantly higher CAP, which did not decrease significantly during detoxification. Conclusions: CAP has a good diagnostic accuracy for diagnosing severe alcoholic liver steatosis and can be used to rule in any steatosis. In non-obese but not in obese, patients, CAP rapidly declines after alcohol withdrawal. Lay summary: CAP is a new ultrasound-based technique for measuring fat content in the liver, but has never been tested for fatty liver caused by alcohol. Herein, we examined 562 patients in a multicentre setting. We show that CAP highly correlates with liver fat, and patients with a CAP value above 290 dB/m were highly likely to have more than 5% fat in their livers, determined by liver biopsy. CAP was also better than regular ultrasound for determining the severity of alcoholic fatty-liver disease. Finally, we show that three in four (non-obese) patients rapidly decrease in CAP after short-term alcohol withdrawal. In contrast, obese alcohol-overusing patients were more likely to have higher CAP values than lean patients, irrespective of drinking.

Background & Aims Controlled attenuation parameter (CAP) can be performed together with liver stiffness measurement (LSM) by transient elastography (TE) and is often used to diagnose fatty liver. We aimed to define the validity criteria of CAP. Methods CAP was measured by the M probe prior to liver biopsy in 754 consecutive patients with different liver diseases at three centers in Europe and Hong Kong (derivation cohort, n = 340; validation cohort, n = 414; 101 chronic hepatitis B, 154 chronic hepatitis C, 349 non-alcoholic fatty liver disease, 37 autoimmune hepatitis, 49 cholestatic liver disease, 64 others; 277 F3-4; age 52 ± 14; body mass index 27.2 ± 5.3 kg/m2). The primary outcome was the diagnosis of fatty liver, defined as steatosis involving ≥5% of hepatocytes. Results The area under the receiver-operating characteristics curve (AUROC) for CAP diagnosis of fatty liver was 0.85 (95% CI 0.82–0.88). The interquartile range (IQR) of CAP had a negative correlation with CAP (r = −0.32, p

Background & Aims: Chronic liver diseases (CLD) are common, and are therefore mainly managed by non-hepatologists. These physicians lack access to the best non-invasive tests of liver fibrosis, and consequently cannot accurately determine the disease severity. Referral to a hepatologist is then needed. We aimed to implement an algorithm, comprising a new first-line test usable by all physicians, for the detection of advanced liver fibrosis in all CLD patients. Methods: Diagnostic study: 3754 CLD patients with liver biopsy were 2: 1 randomized into derivation and validation sets. Prognostic study: longitudinal follow-up of 1275 CLD patients with baseline fibrosis tests. Results: Diagnostic study: the easy liver fibrosis test (eLIFT), an "at-a-glance" sum of points attributed to age, gender, gammaglutamyl transferase, aspartate aminotransferase (AST), platelets and prothrombin time, was developed for the diagnosis of advanced fibrosis. In the validation set, eLIFT and fibrosis-4 (FIB4) had the same sensitivity (78.0% vs. 76.6%, p = 0.470) but eLIFT gave fewer false positive results, especially in patients >= 60 years old (53.8% vs. 82.0%, p < 0.001), and was thus more suitable as screening test. FibroMeter with vibration controlled transient elastography (VCTE) was the most accurate among the eight fibrosis tests evaluated. The sensitivity of the eLIFT-FMVCTE algorithm (first-line eLIFT, second-line FibroMeter(VCTE)) was 76.1% for advanced fibrosis and 92.1% for cirrhosis. Prognostic study: patients diagnosed as having "no/mild fibrosis" by the algorithm had excellent liver-related prognosis with thus no need for referral to a hepatologist. Conclusion: The eLIFT-FMVCTE algorithm extends the detection of advanced liver fibrosis to all CLD patients and reduces unnecessary referrals of patients without significant CLD to hepatologists. Lay summary: Blood fibrosis tests and transient elastography accurately diagnose advanced liver fibrosis in the large population of patients having chronic liver disease, but these noninvasive tests are only currently available in specialized centers. We have developed an algorithm including the easy liver fibrosis test (eLIFT), a new simple and widely available blood test. It is used as a first-line procedure that selects at-risk patients who need further evaluation with the FibroMeter(VCTE), an accurate fibrosis test combining blood markers and transient elastography result. This new algorithm, called the eLIFT-FMVCTE, accurately identifies the patients with advanced chronic liver disease who need referral to a specialist, and those with no or mild liver lesions who can remain under the care of their usual physician. Clinical trial registration: No registration (analysis of pooled data from previously published diagnostic studies). (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background & Aims Liver fibrosis stage is traditionally assessed with biopsy, an imperfect gold standard. Two widely used techniques, FibroTest®, and liver stiffness measurement (LSM) using Fibroscan® have been validated using biopsy, and therefore the true performances of these estimates are still unknown in the absence of a perfect reference. The aim was to assess the relative accuracy of FibroTest, LSM, and biopsy using methods without gold standard in patients with chronic hepatitis C (CHC) and controls. Methods A total of 1289 patients with CHC and 604 healthy volunteers, with assessment of fibrosis stage by the three techniques, and alanine aminotransferase (ALT) taken as a control test, were analyzed by latent class method with random effects. In the volunteers, the false positive risk of biopsy was obtained from a large surgical sample of four normal livers. Results The latent class model with random effects permitted to conciliate the observed data and estimates of test performances. For advanced fibrosis, the specificity/sensitivity was for FibroTest 0.93/0.70, LSM 0.96/0.45, ALT 0.79/0.78 and biopsy 0.67/0.63, and for cirrhosis FibroTest 0.87/0.41, LSM 0.93/0.39, ALT 0.78/0.08 and biopsy 0.95/0.51. The analysis of the discordances between pairs suggested that the variability of the model was mainly related to the discordances between biopsy and LSM (residuals>10; p Conclusions A method without the use of a gold standard confirmed the accuracy of FibroTest and Fibroscan for the diagnosis of advanced fibrosis and cirrhosis in patients with chronic hepatitis C. The variability of the model was mostly due to the discordances between Fibroscan and biopsy.

Background & Aims Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (FibroScan) and FibroTest could be useful for monitoring MTX–liver toxicity. The aim of this case–control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX. Methods Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and FibroTest when they were treated with MTX (cases) or before beginning treatment (controls). Results Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28kg/m2 and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results. Conclusions Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.

Background/Aims Transient elastometry (TE) is accurate for detecting cirrhosis ( F =4) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. However, this procedure is less precise to differentiate mild ( F ⩽1) from moderate to severe ( F ⩾2) fibrosis using the cut-off value of 7.2kPa, a level previously proposed by some authors. Because of this, we elaborated and validated cut-off values of liver stiffness (LS) to better discriminate F ⩽1 from F ⩾2 in HIV/HCV co-infected subjects to aid therapy decisions. Methods One hundred and ninety-seven co-infected patients with liver biopsy and TE measurement, without prior therapy against HCV infection, were included. Results To diagnose F ⩾2, a cut-off of 9.0kPa showed a positive predictive value of 87%. To discard F ⩾2, a cut-off of 6.0kPa showed a negative predictive value of 90%. Considering all the patients, 61 (31%) patients yielded LS values ⩽6.0kPa and 81 (41%) patients showed LS values ⩾9.0kPa. There were no severe classification errors as the NPV of LS⩽6.0kPa for F ⩾3 was 100% and the NPV LS ⩾9.0kPa for F =0 was also 100%. Conclusions The usefulness of TE can be enhanced using two different cut-off values to identify patients with F ⩽1 and F ⩾2.

Background/Aims The aim of this study was to describe the natural history of a HCV infection outbreak in 196 patients who had sclerotherapy by a same physician and to confirm patient-to-patient transmission using phylogenetic analysis in a large series of patients. Methods Demographic information included clinical and biological parameters. Fibrosis evaluation was performed using liver biopsy or transient elastography. Follow-up was maintained until death, or the end of the observation period. In order to determine if the virus had been transmitted between the HCV genotype 2 patients, sequence analysis was undertaken of a part of the NS5b region of the genomes in samples of patients. Results The mean duration of follow-up was 23.1±6.7 years (4535 patient-years). In patients with fibrosis evaluation, 55.7% had no or mild fibrosis and 44.3% had significant fibrosis. No patient died from HCV-related disease. Nucleotide sequence analysis of a part of the NS5b region revealed that patients were all infected with the same HCV subtype (genotype 2d). The most evident feature of the tree is the clustering of all patients involved in the outbreak without any unrelated isolates. Conclusion This study emphasizes the risk for nosocomial spread of HCV during intravenous therapy.

We compared the efficacy and safety of the combined therapy of daily interferon alpha-2b and ribavirin with those of interferon alpha-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection.A total of 376 patients were randomly assigned to receive interferon alpha-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon alpha-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C).After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.

Background/Aims : Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. Methods : We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). Results : The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) ( P =0.0001 and P =0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. Conclusions : Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.

Background & Aims Unreliable results of liver stiffness measurement are obtained in 16% of cases and are independently associated with body mass index (BMI) greater than 30kg/m 2 . A new FibroScan® probe (XL probe) was designed specifically for obese patients. The aim of this study was to evaluate the accuracy of liver stiffness measurement using M and XL probes of Fibroscan® for the diagnosis of fibrosis and cirrhosis in a large cohort of patients. Methods Consecutive patients undergoing liver biopsies for chronic liver disease were prospectively recruited. Liver stiffness measurement was performed within 1week before liver biopsy using both M and XL probes of FibroScan®. Results A total of 286 patients were evaluated. A reliable liver stiffness measurement using M probe was obtained in 79.7% of cases. In the other 21.3%, liver stiffness measurement using XL probe was obtained in 56.9% of patients. A strong correlation was found between M and XL values, regardless of BMI. In all groups, median liver stiffness measurement using the XL probe was significantly lower than liver stiffness measurement using the M probe. By multivariate analysis, unsuccessful liver stiffness examination with M probe was independently associated with age >50years and BMI >30kg/m 2 . By univariate analysis, only BMI >30kg/m 2 was associated with unsuccessful liver stiffness measurement with XL probe. No significant difference was observed between the M and XL probes for the diagnosis of liver fibrosis. Conclusions Liver stiffness measurement with either M or XL probe is possible in 91.2% of patients with comparable diagnostic accuracy. In clinical practice, the M probe could be used as first step for liver stiffness measurement. In case of no valid shot or unreliable measurement, the XL probe could be used. This result could be useful for the assessment of liver fibrosis in NAFLD and/or obese patients.

The aim of this study was to assess the accuracy of liver stiffness measurement (LSM) for the diagnosis of extensive fibrosis and cirrhosis in patients with alcoholic liver disease (ALD).One hundred and seventy-four patients with ALD were enrolled in four liver units and underwent concomitant liver biopsy and LSM. Fibrosis was assessed using the Brunt et al. and the Chevallier et al. scoring systems. Steatosis and histological alcoholic hepatitis (HAH) were quoted in classes.Twenty-seven patients had inadequate biopsy or LSM. Distribution in 147 patients according to the Brunt score (median LSM) was: F1: n=13 (5.7kPa); F2: n=24 (8.3kPa); F3: n=31 (17.5kPa) and F4: n=79 (40.9kPa) (P0.0001). LSM was correlated with the amount of fibrosis according to the Chevallier score (r=0.70, P0.0001). LSM was correlated to fibrosis stage (tau beta, 0.53; P0.0001) and HAH (tau beta, 0.30; P0.0001). In multivariate analysis, fibrosis was the only parameter correlated with LSM. The areas under the ROC curve were 0.94 and 0.87 for the diagnosis of extensive fibrosis (Brunt et al. scoreor =3) and cirrhosis, respectively (threshold-values: 12.9 and 22.6kPa).LSM accurately assesses extensive fibrosis and cirrhosis in alcoholic patients.

To assess prospectively the accuracy of transient elastography (TE, FibroScan) for the detection of cirrhosis and oesophageal varices (OV) in chronic hepatitis C (CHC), as compared with currently available non-invasive methods (AST/ALT ratio (AAR), APRI, prothrombin index (PI), platelet count (PC), FibroTest (FT) and Lok index).All tests were performed the day of liver biopsy (LB), taken as reference, in 298 consecutive CHC patients (cirrhosis: 70; Child-Pugh A: 70; OV: 25).TE had the best diagnostic accuracy for detection of cirrhosis (AUROCs: TE 0.96 vs. FT 0.82, Lok and APRI 0.80, PC 0.79, PI 0.73, AAR 0.61, respectively; p0.0001). Overall, the percentage of saved LB was: TE (cut-off: 12.5 kPa) 90%, PC 82%, FT 79%, PI 77%, AAR 76%, APRI 70%, and Lok 45%, respectively. At a cut-off of 21.5 kPa, TE predicted the presence of OV with 76% sensitivity and 78% specificity and correctly classified 73% of patients vs. AAR 81%, Lok 77%, FT, PI 70%, PC 69%, and APRI 66%, respectively.TE is currently the most accurate non-invasive method for early detection of cirrhosis in CHC (cut-off: 12.5 kPa), as compared with other available methods, but cannot replace endoscopy for OV screening.

Background/Aims FibroScan ® , a non-invasive procedure for the diagnosis of cirrhosis, benefits only patients for which at least 10 valid shots are acquired. We investigated features associated with success rate of shots, and performance of FibroScan ® for the diagnosis of cirrhosis. Methods Liver biopsy and stiffness measurement were performed in HCV patients. AUROCs and mixed logistic models evaluated the influence of patient and operator features on the success of shots and the performance for the diagnosis of cirrhosis. Results Nine hundred and thirty five (935) patients were included. Success rate of shots decreased with age, and was lower in obese than in other patients. After adjusting for age and obesity, an operator with at least 50 prior FibroScan ® exams had a higher success rate in shots. FibroScan ® performance for the diagnosis of cirrhosis was not influenced by the number of valid shots taken into account and by operator skills. Conclusions After a rapid training, FibroScan ® provides a reasonable performance for the diagnosis of cirrhosis that is not influenced substantially by any other feature. More patients will benefit from this procedure with no significant loss in performance if only 5 valid shots are requested. These results should emphasize the use of FibroScan ® even in non-specialized units.

Background/Aims In patients with unexplained elevated transaminases, prognosis of the liver disease and factors associated with increased risk of liver fibrosis and normal/subnormal liver are unknown. The aim of this prospective study was to identify diagnosis and clinical and biological factors associated with significant (bridging) fibrosis and minimal lesions of the liver in patients with persistent unexplained elevated ALT levels. Methods From July 2002 through October 2004, all consecutive asymptomatic patients with unexplained chronically elevated ALT levels were included. All patients had clinical, biological, ultrasonographic examination and a liver biopsy. Results 272 patients (60.3% males, mean age 46.4 years, BMI 26.7) were included. Pathological findings were: minimal lesions (18.7%), steatosis (26.8%), NASH (32.7%), and miscellaneous (21.7%). Significant fibrosis was found in 27.4% of cases, including 9 cases of cirrhosis. By multivariate analysis, independent predictors of significant fibrosis were tobacco use (OR 2.5, 95% CI 1.34–4.74 p =0.04), BMI>25 (2.49, 1.31–4.73 p =0.005) and diabetes (4.41, 1.73–11.29 p =0.002). Independent factors associated with minimal lesions were female gender (OR 3.4 95% CI 1.73–6.75 p p Conclusions In patients with unexplained chronically elevated transaminases, significant fibrosis is statistically associated with tobacco use, BMI>25 and diabetes, and minimal lesions are significantly associated with female gender and BMI

Background/Aims: We have shown that hepatocyte growth factor secreted by human hepatic myofibroblastsincreased the in vitro invasion of the hepatocarcinoma cell line HepG2 through Matrigel. Our aim in this study was to evaluate the role of urokinase in this process. Methods: Expression of urokinase in HepG2 cells was measured by Northern blot and zymography, and plasminogen activation was shown by a chromogenic substrate assay. Cell invasion was assayed on Matrigelcoated filters. Urokinase and urokinase receptor transcripts in hepatocarcinoma were detected by reverse transcription-polymerase chain reaction. Activated hepatocyte growth factor was detected by Western blot with a hepatocyte growth factor-β chain-specific antibody. Results: HepG2 cells expressed urokinase mRNA and secreted active urokinase. Urokinase expression was enhanced by hepatocyte growth factor at the protein and mRNA level. Notably, cell-surface-associated urokinase was increased 22-fold by hepatocyte growth factor. Hepatocyte growth factor also increased urokinase receptor mRNA expression. B428, a urokinase inhibitor, decreased by up to 70% HepG2 invasion induced by myofibroblasts and by 90% that induced by recombinant hepatocyte growth factor. This was not due to a decrease in the generation of activated hepatocyte growth factor by myofibroblasts. Finally, all 17 hepatocarcinoma samples tested expressed urokinase and urokinase receptor transcripts. Conclusion: Hepatocyte growth factor-dependent, myofibroblasts-induced invasion of HepG2 cells is secondary to the induction of urokinase expression on tumor cells.

Background/Aim: The aim of this case-control study was to assess the risk of bleeding from esophageal varices associated with aspirin and non-steroidal anti-inflammatory drug consumption. Methods: Between January 1992 and May 1994, patients admitted for bleeding from esophageal or gastric lesions related to portal hypertension were matched with a control patients of the same age and sex, who was free of gastrointestinal bleeding. A structured interview was conducted with the cases and controls to determine drug consumption during the 2 weeks preceding admission. Fifty-nine cases and 59 controls were recruited. Results/Conclusions: Use of aspirin was more prevalent among the cases than the controls (odds ratio 3.81; 95% confidence interval 1.36–11.64; p =0.004). This difference remained significant in the subgroups of patients with a first episode of variceal bleeding (odds ratio 3.9; 95% confidence interval 1.2–13.9, p =0.01), but was not significant in the subgroups of patients with a recurrent episode of variceal bleeding. The use of aspirin was associated with a high risk of a first episode of variceal bleeding, suggesting that patients with portal hypertension should avoid taking these drugs.

Summary Background FibroTest ® (FT), and liver stiffness measurement (LSM) are the most validated techniques for the non-invasive assessment of fibrosis in patients with chronic hepatitis C (CHC). The combination between FibroTest ® and LSM has never been assessed using methods assuming that biopsy is not a perfect gold standard. Aim The aim was to assess the performance of a new test the Elasto-FibroTest ® (EFT) combining FibroTest ® and LSM. Methods An integrated data base of 1289 patients with biopsy and 604 healthy volunteers was analyzed. EFT took into account the applicability of both tests, included two algorithms taking one for the diagnosis of advanced fibrosis (EFT-F2) and one for the diagnosis of cirrhosis (EFT-F4). Performances of EFTs were assessed by three methods: area under the ROC curve (AUROC), “Obuchowski method” (OBU) and 1 TAGS the “Latent class with random factor”. Results For the diagnosis of advanced fibrosis EFT-F2 performances (specificity = 0.99 and sensitivity = 0.83) were not greater than the performances of FibroTest ® alone (specificity = 0.93 and sensitivity = 0.99). For the diagnosis of cirrhosis, EFT-F4 performances were greater than those of FibroTest ® alone, particularly for the sensitivity (0.88 vs. 0.74); when compared with LSM, EFT-F4 performances (specificity = 0.99 and sensitivity = 0.99) were also greater than those of LSM alone particularly because of its lower specificity (0.92). Conclusion For the diagnosis of cirrhosis the Elasto-FibroTest ® has higher performances than FibroTest ® or FibroScan ® alone. No improvement in performance has been observed for the diagnosis of advanced fibrosis vs. FibroTest ® alone.