M. Munteanu

Assessment of liver fibrosis: noninvasive means.

Liver biopsy, owing to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases chronic hepatitis C (HCV), B (HBV) non alcoholic (NAFLD) and alcoholic (ALD) fatty liver diseases. This review summarizes the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2,237 references, a total of 14 validated serum biomarkers have been identified between 1991 and 2008. Nine were not patented and five were patented. Two alternatives to liver biopsy were the most evaluated FibroTest and Fibroscan. For FibroTest, there was a total of 38 different populations including 7,985 subjects with both FibroTest and biopsy (4,600 HCV, 1,580 HBV, 267 NAFLD, 524 ALD, and 1014 mixed). For Fibroscan, there was a total of 11 published studies including 2,260 subjects (1,466 HCV, 95 cholestatic liver disease, and 699 mixed). For FibroTest, the mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the ROC curves was 0.84 (95% confidence interval 0.83-0.86), without a significant difference between the causes of liver disease, hepatitis C, hepatitis B, and alcoholic or non alcoholic fatty liver disease. High-risk profiles of false negative/false positive of FibroTest, mainly Gilbert syndrome, hemolysis and acute inflammation, are present in 3% of the populations. In case of discordance between biopsy and FibroTest, half of the failures can be due to biopsy; the prognostic value of FibroTest is at least similar to that of biopsy in HCV, HBV and ALD. In conclusion this overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the first line assessment of fibrosis stage in the four most common chronic liver diseases, namely HCV, HBV, NAFLD and ALD. Neither biomarkers nor biopsy alone is sufficient for taking a definite decision in a given patient; all the clinical and biological data must be taken into account. There is no evidence based data justifying biopsy as a first line estimate of liver fibrosis. Health authorities in some countries have already approved validated biomarkers as the first line procedure for the staging of liver fibrosis.

Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: An overview of published trials

BACKGROUND The impact of interferon treatment in patients with hepatitis B virus (HBV) infection on fibrosis progression in comparison with its natural history has yet to be assessed in any large-scale randomized studies. The present report is a review of the evidence-based data published so far. METHODS Studies were included if they had at least two repeated estimates of liver fibrosis per patient treated with interferon-alpha (whether pegylated or not). Meta-analysis was performed using a random-effects model. RESULTS Altogether, 13 studies were included in the review, involving a total of 707 HBV patients treated with interferon-alpha-2a or -2b for 12-83 months. Only one study included pegylated interferon as monotherapy. A total of 787 untreated patients were also followed. Only one study used a non-invasive biomarker. There was a significant reduction in the fibrosis progression rate, with a risk reduction of 0.49 (95% CI: -0.64--0.34; chi(2)=119; degrees of freedom [DF]=6; P<0.0001), and significant heterogeneity (Cochran Q=81; P<0.0001). This significant impact was similar for both randomized (reduction of risk: -0.45; 95% CI: -0.64--0.26; P<0.0001) and not-randomized (controlled) studies (reduction of risk: -0.53; 95% CI: -0.79--0.28; P<0.0001). CONCLUSION According to these findings, the benefit of interferon treatment on fibrosis progression is clinically significant in patients with advanced fibrosis by the reduction of fibrosis progression to cirrhosis. Pegylated interferon now needs to be compared, in terms of benefit-risk factors, with the new generation of HBV treatments (such as entecavir and tenofovir), using non-invasive biomarkers.

Optimal correlation between different instruments for Fibrotest-Actitest protein measurement in patients with chronic hepatitis C

OBJECTIVES Combination of alpha 2-macroglobulin, haptoglobin, apolipoprotein-A1, gamma-glutamyl transpeptidase, total bilirubin and alanine aminotransferase measurements allows to determine the Fibrotest-Actitest score, an alternative to liver biopsy in hepatitis C virus infection. The aims of this study were to evaluate the analytical variability of the Fibrotest-Actitest proteins alpha 2-macroglobulin, haptoglobin and apolipoprotein-A1, and to assess their impact on the Fibrotest-Actitest scores. METHODS We compared 129 sera from hepatitis C virus infected patients for alpha 2-macroglobulin, haptoglobin and apolipoprotein-A1 levels obtained with the Immage (Beckman-Coulter) and the BNProspec (Dade-Berhing) automates. We evaluated Fibrotest-Actitest results obtained with the two nephelemeters. RESULTS Optimal correlation was found for alpha 2-macroglobulin (Y=1.05X + 0.01, correlation coefficient: 0.98) and haptoglobin (Y=1.05X - 0.07, correlation coefficient: 0.98). Apolipoprotein-A1 levels, as determined by Immage, were slightly lower than those obtained by BNProspec (Y=0.86X - 0.02, CC=0.95). When Fibrotest-Actitest scores obtained with the two protein measurements were compared adjusting for apolipoprotein-A1 from Immage, the concordance rate was 0.903+/-0.096, with only 2/107 patients showing minimal discordance>0.10 for Fibrotest, and 1.00+/-0.06 for Actitest, with no discordance>0.10. CONCLUSIONS Measurement of apolipoprotein-A1, included in the Fibrotest-Actitest score, depends on the equipment used. Such discordance is of little clinical consequence for liver fibrosis evaluation in hepatitis C virus patients.