Independent validation of the Enhanced Liver Fibrosis (ELF) score in the ANRS HC EP 23 Fibrostar cohort of patients with chronic hepatitis C

BACKGROUND: The Enhanced Liver Fibrosis (ELF) score combining serum hyaluronan, N-terminal peptide of type III procollagen and tissue inhibitor of metalloproteinase-1, was reported as relevant in predicting liver fibrosis in chronic liver disease and proposed as an alternative to liver biopsy. METHODS: We evaluated the ELF score in a cohort of chronic hepatitis C (CHC) patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using commercial reagents, different from those developed by the manufacturer of the Siemens ELF™ test. RESULTS: In 512 CHC, the ELF score, using ROC curves, showed good predictive performances for severe fibrosis [AUROC=0.82; 95% confidence interval (CI) 0.78-0.86]and for cirrhosis (AUROC=0.85; 95% CI 0.81-0.90), but slightly lower for significant fibrosis (AUROC=0.78; 95% CI 0.74-0.82). The Obuchowski measure (0.81) showed that the ELF score globally performed as a marker of liver fibrosis. The ELF score predicted significant fibrosis (cut-off=9.0) with a sensitivity of 0.86, a specificity of 0.62, a positive predictive value (PPV) of 0.80 and a negative predictive value (NPV) of 0.70. For extensive fibrosis (cut-off=9.33), sensitivity was 0.90, specificity was 0.63, PPV was 0.73 and NPV was 0.85. For cirrhosis (cut-off=9.35), sensitivity was 0.83, specificity was 0.75, PPV was 0.44 and NPV was 0.95. CONCLUSIONS: This study confirms the ELF score performance as an index to predict liver fibrosis or cirrhosis in CHC. The ELF test, using validated reagents, could be added to the health authorities approved non-invasive tests in assessing fibrosis as surrogate to liver biopsy

AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations.

OBJECTIVE: The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. METHODS: ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5\u27-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. RESULTS: AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, P<0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F≥2) (AUROC=0.531) and had only very poor diagnostic accuracies for severe fibrosis (F≥3) (AUROC=0.584) or cirrhosis (F4) (AUROC=0.626). CONCLUSION: AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations

Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy

BACKGROUND: Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. METHODS: Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. RESULTS: Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. CONCLUSION: Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value

Automation of the Hepascore and validation as a biochemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort

Background Hepascore combining serum bilirubin, gamma glutamyl transpeptidase, hyaluronic acid (HA) and α2-macroglobulin with age and sex, was reported as relevant in predicting liver fibrosis in patients with chronic HCV infection and was proposed as an alternative to liver biopsy. Methods Since an automated HA assay (Latex method, Wako, Japan) became available, we investigated to automate Hepascore by simultaneous measurements of components using an OLYMPUS AU640 analyzer (Tokyo, Japan). For its clinical evaluation, we considered a cohort of chronic HCV patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar). Results Automated Hepascore was not significantly different than assayed as previously described. An improvement in HA variability was evidenced. In 512 chronic HCV patients, automated Hepascore, using ROC curves analysis, showed good predictive performances for significant fibrosis (AUROC = 0.81), severe fibrosis (AUROC = 0.82), and cirrhosis (AUROC = 0.88). For significant fibrosis, Hepascore (cut-off = 0.5) had a sensitivity of 0.77, a specificity of 0.70, a positive predictive value of 0.71 and a negative predictive value (NPV) of 0.77. Hepascore < 0.25 could exclude significant fibrosis with a sensitivity of 0.95 and a NPV of 0.90 and Hepascore < 0.75 could exclude cirrhosis with a sensitivity of 0.86 and a NPV of 0.97. Conclusions This study shows that Hepascore, a non-invasive index of liver fibrosis, necessitating only one serum sample, can be totally automated using a single analyzer and confirms that Hepascore accurately predicts liver fibrosis in chronic HCV. Hepascore might be largely used in assessing liver fibrosis as surrogate to the liver biopsy

Assessment of new hyaluronic acid assays and their impact on FibroMeter scores

BackgroundWe compared three hyaluronic acid (HA) assays and analyzed the impact of their variations on FibroMeter scores. Methods In a test group of 165 patients, HA levels were assessed with the commonly used ELISA assay from Corgenix, a new ELISA assay from Teco and an immunoturbidimetry assay from Wako, this latter tested across three different instruments. Five different FibroMeter scores were calculated. Results Correlation across the three assays (rs between 0.969 and 0.995) was very good. Means of differences (d) were lower when the immunoturbidimetry assay was compared on different instruments: d between −3.4 and 2.0 μg/L. However, a higher value for HA measurement was observed with Corgenix assay, compared to the other two assays (Teco and Wako): d between 27.1 and 36.4 μg/L. The assessment also demonstrated that HA variations had very little impact on FibroMeter scores: 0.0117 for virus and 0.0416 for alcoholic fibrosis scores, and between 0.58 and 1.71 for the area of fibrosis (expressed in percentage). Conclusions The two new assays found lower values of HA, as compared to the Corgenix assay. However, these differences had very little impact on FibroMeter scores and had no impact on clinical evaluation of liver fibrosis

Liver-FibroSTARD checklist and glossary: tools for standardized design and reporting of diagnostic accuracy studies of liver fibrosis tests

Chronic liver diseases are highly prevalent and require an accurate evaluation of liver fibrosis to determine patient management. Many efforts have been made over this last decade to develop accurate non-invasive tools for liver fibrosis evaluation as alternative methods to liver biopsy. These non-invasive methods of liver fibrosis assessment including blood markers and liver stiffness measurement by elastography are increasingly well validated and contribute to safer and more practical clinical care for patients [1, 2]. These efforts have led to a dramatic increase in the number of diagnostic accuracy studies of liver fibrosis tests and to a proliferation of reports whose quality is very heterogeneous. [...

An extension of STARD statements for reporting diagnostic accuracy studies on liver fibrosis tests: the Liver-FibroSTARD standards

BACKGROUND & AIMS: Chronic liver diseases are highly prevalent and require an accurate evaluation of liver fibrosis to determine patient management. Over the last decade, great effort has been made to develop non-invasive liver fibrosis tests. The ensuing increase of literature is, however, impaired by extensive heterogeneity in the quality of published reports. The Standards for Reporting of Diagnostic Accuracy Studies (STARD), first published in 2003, were developed to improve the quality of research reports on diagnostic studies. We aimed to evaluate STARD statements in the setting of diagnostic studies on non-invasive liver fibrosis tests, and to propose an extended version developed specifically for those studies. METHODS: Eight French experts evaluated STARD statement adequacy in 10 studies on non-invasive liver fibrosis tests and then developed an extended version with a glossary. The new checklist and glossary were independently evaluated by seven international experts. RESULTS: Fourteen of the 25 STARD items were considered only partially adequate for the evaluation of diagnostic studies on non-invasive liver fibrosis tests. Inter-expert agreement was at least very good for 8 STARD items (32%), moderate for 9 (36%), and poor or very poor for 8 (32%). The experts\u27 proposals were developed into the new Liver-FibroSTARD standards including a checklist with 62 items/sub-items and a corresponding comprehensive glossary. New proposals were inserted in the 25 STARD items as a complementary module. Independent evaluation of the Liver-FibroSTARD checklist showed at least very good inter-expert agreement for 39 items/sub-items (63%), moderate agreement for 11 (18%), and poor or very poor agreement for only 12 (19%). CONCLUSIONS: As a supplement of the STARD statements, the Liver-FibroSTARD checklist and its glossary are new tools specifically designed for the evaluation of diagnostic studies about non-invasive liver fibrosis tests