Cirrhosis Diagnosis and Liver Fibrosis Staging: Transient Elastometry Versus Cirrhosis Blood Test.

INTRODUCTION: Elastometry is more accurate than blood tests for cirrhosis diagnosis. However, blood tests were developed for significant fibrosis, with the exception of CirrhoMeter developed for cirrhosis. We compared the performance of Fibroscan and CirrhoMeter, and classic binary cirrhosis diagnosis versus new fibrosis staging for cirrhosis diagnosis. METHODS: The diagnostic population included 679 patients with hepatitis C and liver biopsy (Metavir staging and morphometry), Fibroscan, and CirrhoMeter. The prognostic population included 1110 patients with chronic liver disease and both tests. RESULTS: Binary diagnosis: AUROCs for cirrhosis were: Fibroscan: 0.905; CirrhoMeter: 0.857; and P=0.041. Accuracy (Youden cutoff) was: Fibroscan: 85.4%; CirrhoMeter: 79.2%; and P<0.001. Fibrosis classification provided 6 classes (F0/1, F1/2, F2±1, F3±1, F3/4, and F4). Accuracy was: Fibroscan: 88.2%; CirrhoMeter: 88.8%; and P=0.77. A simplified fibrosis classification comprised 3 categories: discrete (F1±1), moderate (F2±1), and severe (F3/4) fibrosis. Using this simplified classification, CirrhoMeter predicted survival better than Fibroscan (respectively, χ=37.9 and 19.7 by log-rank test), but both predicted it well (P<0.001 by log-rank test). Comparison: binary diagnosis versus fibrosis classification, respectively, overall accuracy: CirrhoMeter: 79.2% versus 88.8% (P<0.001); Fibroscan: 85.4% versus 88.2% (P=0.127); positive predictive value for cirrhosis by Fibroscan: Youden cutoff (11.1 kPa): 49.1% versus cutoffs of F3/4 (17.6 kPa): 67.6% and F4 classes (25.7 kPa): 82.4%. CONCLUSIONS: Fibroscan\u27s usual binary cutoffs for cirrhosis diagnosis are not sufficiently accurate. Fibrosis classification should be preferred over binary diagnosis. A cirrhosis-specific blood test markedly attenuates the accuracy deficit for cirrhosis diagnosis of usual blood tests versus transient elastometry, and may offer better prognostication

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

Rearing conditions and life history influence the progress of gametogenesis and reproduction performances in pikeperch males and females

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Comparison of accuracy of fibrosis degree classifications by liver biopsy and non-invasive tests in chronic hepatitis C

<p>Abstract</p> <p>Background</p> <p>Non-invasive tests have been constructed and evaluated mainly for binary diagnoses such as significant fibrosis. Recently, detailed fibrosis classifications for several non-invasive tests have been developed, but their accuracy has not been thoroughly evaluated in comparison to liver biopsy, especially in clinical practice and for Fibroscan. Therefore, the main aim of the present study was to evaluate the accuracy of detailed fibrosis classifications available for non-invasive tests and liver biopsy. The secondary aim was to validate these accuracies in independent populations.</p> <p>Methods</p> <p>Four HCV populations provided 2,068 patients with liver biopsy, four different pathologist skill-levels and non-invasive tests. Results were expressed as percentages of correctly classified patients.</p> <p>Results</p> <p>In population #1 including 205 patients and comparing liver biopsy (reference: consensus reading by two experts) and blood tests, Metavir fibrosis (F_M) stage accuracy was 64.4% in local pathologists vs. 82.2% (p < 10^-3) in single expert pathologist. Significant discrepancy (≥ 2F_Mvs reference histological result) rates were: Fibrotest: 17.2%, FibroMeter^2G: 5.6%, local pathologists: 4.9%, FibroMeter^3G: 0.5%, expert pathologist: 0% (p < 10^-3). In population #2 including 1,056 patients and comparing blood tests, the discrepancy scores, taking into account the error magnitude, of detailed fibrosis classification were significantly different between FibroMeter^2G(0.30 ± 0.55) and FibroMeter^3G(0.14 ± 0.37, p < 10^-3) or Fibrotest (0.84 ± 0.80, p < 10^-3). In population #3 (and #4) including 458 (359) patients and comparing blood tests and Fibroscan, accuracies of detailed fibrosis classification were, respectively: Fibrotest: 42.5% (33.5%), Fibroscan: 64.9% (50.7%), FibroMeter^2G: 68.7% (68.2%), FibroMeter^3G: 77.1% (83.4%), p < 10^-3(p < 10^-3). Significant discrepancy (≥ 2 F_M) rates were, respectively: Fibrotest: 21.3% (22.2%), Fibroscan: 12.9% (12.3%), FibroMeter^2G: 5.7% (6.0%), FibroMeter^3G: 0.9% (0.9%), p < 10^-3(p < 10^-3).</p> <p>Conclusions</p> <p>The accuracy in detailed fibrosis classification of the best-performing blood test outperforms liver biopsy read by a local pathologist, i.e., in clinical practice; however, the classification precision is apparently lesser. This detailed classification accuracy is much lower than that of significant fibrosis with Fibroscan and even Fibrotest but higher with FibroMeter^3G. FibroMeter classification accuracy was significantly higher than those of other non-invasive tests. Finally, for hepatitis C evaluation in clinical practice, fibrosis degree can be evaluated using an accurate blood test.</p

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

Determination of reliability criteria for liver stiffness evaluation by transient elastography

UNLABELLED: Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% versus 81.5% well-classified patients for the diagnosis of cirrhosis (P = 0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of ≥10 valid measurements or LSE success rate. These two reliability criteria determined three LSE groups: "very reliable" (IQR/M ≤0.10), "reliable" (0.10&lt; IQR/M ≤0.30, or IQR/M &gt;0.30 with LSE median &lt;7.1 kPa), and "poorly reliable" (IQR/M &gt;0.30 with LSE median ≥7.1 kPa). The rates of well-classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (P &lt; 10(-3) ). According to these new reliability criteria, 9.1% of LSE were poorly reliable (versus 24.3% unreliable LSE with the usual definition, P &lt; 10(-3) ), 74.3% were reliable, and 16.6% were very reliable. CONCLUSION: The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: very reliable, reliable, and poorly reliable LSE. (HEPATOLOGY 2013)

Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive

The sequential algorithm for fibrosis evaluation (SAFE) and the Bordeaux algorithm (BA), which cross-check FibroTest with the aspartate aminotransferase-to-platelet ratio index (APRI) or FibroScan, are very accurate but provide only a binary diagnosis of significant fibrosis (SAFE or BA for Metavir F ≥ 2) or cirrhosis (SAFE or BA for F4). Therefore, in clinical practice, physicians have to apply the algorithm for F ≥ 2, and then, when needed, the algorithm for F4 (“successive algorithms”). We aimed to evaluate successive SAFE, successive BA, and a new, noninvasive, detailed classification of fibrosis. The study included 1785 patients with chronic hepatitis C, liver biopsy, blood fibrosis tests, and FibroScan (the latter in 729 patients). The most accurate synchronous combination of FibroScan with a blood test (FibroMeter) provided a new detailed (six classes) classification (FM+FS). Successive SAFE had a significantly (P &lt; 10−3) lower diagnostic accuracy (87.3%) than individual SAFE for F ≥ 2 (94.6%) or SAFE for F4 (89.5%), and required significantly more biopsies (70.8% versus 64.0% or 6.4%, respectively, P &lt; 10−3). Similarly, successive BA had significantly (P ≤ 10−3) lower diagnostic accuracy (84.7%) than individual BA for F ≥ 2 (88.3%) or BA for F4 (94.2%), and required significantly more biopsies (49.8% versus 34.6% or 24.6%, respectively, P &lt; 10−3). The diagnostic accuracy of the FM+FS classification (86.7%) was not significantly different from those of successive SAFE or BA. However, this new classification required no biopsy. Conclusion: SAFE and BA for significant fibrosis or cirrhosis are very accurate. However, their successive use induces a significant decrease in diagnostic accuracy and a significant increase in required liver biopsy. A new fibrosis classification that synchronously combines two fibrosis tests was as accurate as successive SAFE or BA, while providing an entirely noninvasive (0% liver biopsy) and more precise (six versus two or three fibrosis classes) fibrosis diagnosis

Quantification of portal–bridging fibrosis area more accurately reflects fibrosis stage and liver stiffness than whole fibrosis or perisinusoidal fibrosis areas in chronic hepatitis C

International audienceMorphometry provides an objective evaluation of fibrosis in liver diseases. We developed an image analysis algorithm using automated thresholding and segmentation to separately quantify the areas and the fractal dimensions of portal–bridging fibrosis and perisinusoidal fibrosis in chronic hepatitis C liver biopsies. We studied 427 digitized liver biopsies and compared the automated measures of the different fibrosis compartments with (1) the Metavir F (fibrosis) and A (activity) histological scores, (2) the digitally assessed area of steatosis, and (3) the liver stiffness measured by elastography (Fibroscan). The perisinusoidal fibrosis area was higher than that of portal fibrosis in stages ≤F2; it reached its highest value in F2 stage and stabilized thereafter. The F3 stage was characterized by equal proportions of portal–bridging and perisinusoidal fibrosis, whereas portal–bridging area was predominant in cirrhosis. Measurement of portal–bridging fibrosis showed highly significantly different values between contiguous F stages; the ratio of portal–bridging fibrosis/perisinusoidal fibrosis displayed less overlap between Metavir stages than did the whole fibrosis area values. Fractal dimension showed that portal–bridging fibrosis tended to display a homogeneous surface-like spatial organization, whereas perisinusoidal fibrosis appeared more heterogeneous according to stage and curvilinear. The portal–bridging fibrosis area was low in cases with low Metavir activity and little steatosis, and became predominant with increasing activity and steatosis. Using stepwise multiple linear regression analysis, the liver stiffness was independently correlated to the portal–bridging fibrosis area (first step, P<0.001), the steatosis area (second step, P<0.001), and the Metavir A grade (third step, P=0.001), but not to the perisinusoidal fibrosis area. Automated quantification in a large cohort of chronic hepatitis C showed that perisinusoidal fibrosis progressively grew in early fibrosis stages but did not increase in septal or cirrhotic stages and that the portal–bridging fibrosis area appeared as a more accurate tool to assess fibrosis progression than the whole fibrosis area

Improved fibrosis staging by elastometry and blood test in chronic hepatitis C.

AIMS: Our main objective was to improve non-invasive fibrosis staging accuracy by resolving the limits of previous methods via new test combinations. Our secondary objectives were to improve staging precision, by developing a detailed fibrosis classification, and reliability (personalized accuracy) determination. METHODS: All patients (729) included in the derivation population had chronic hepatitis C, liver biopsy, 6 blood tests and Fibroscan. Validation populations included 1584 patients. RESULTS: The most accurate combination was provided by using most markers of FibroMeter and Fibroscan results targeted for significant fibrosis, i.e. \u27E-FibroMeter\u27. Its classification accuracy (91.7%) and precision (assessed by F difference with Metavir: 0.62 ± 0.57) were better than those of FibroMeter (84.1%, P &lt; 0.001; 0.72 ± 0.57, P &lt; 0.001), Fibroscan (88.2%, P = 0.011; 0.68 ± 0.57, P = 0.020), and a previous CSF-SF classification of FibroMeter + Fibroscan (86.7%, P &lt; 0.001; 0.65 ± 0.57, P = 0.044). The accuracy for fibrosis absence (F0) was increased, e.g. from 16.0% with Fibroscan to 75.0% with E-FibroMeter (P &lt; 0.001). Cirrhosis sensitivity was improved, e.g. E-FibroMeter: 92.7% vs. Fibroscan: 83.3%, P = 0.004. The combination improved reliability by deleting unreliable results (accuracy &lt;50%) observed with a single test (1.2% of patients) and increasing optimal reliability (accuracy ≥85%) from 80.4% of patients with Fibroscan (accuracy: 90.9%) to 94.2% of patients with E-FibroMeter (accuracy: 92.9%), P &lt; 0.001. The patient rate with 100% predictive values for cirrhosis by the best combination was twice (36.2%) that of the best single test (FibroMeter: 16.2%, P &lt; 0.001). CONCLUSION: The new test combination increased: accuracy, globally and especially in patients without fibrosis, staging precision, cirrhosis prediction, and even reliability, thus offering improved fibrosis staging

Fibrosis progression under maintenance interferon in hepatitis C is better detected by blood test than liver morphometry

Summary.  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 (ric ≥ 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