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Electronic Letters to:
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Electronic letters published:
![[Read eLetter]](/icons/misc/sectionDOWN.gif){kind=icon}
Fibrosis biomarkers are not only a formula
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Thierry Poynard , Vlad Ratziu, Francoise Imbert-Bismut, Mona Munteanu
Send letter to journal:
tpoynard{at}teaser.fr Thierry Poynard, et al.
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Dear Editor We read with great interest the recent paper by Adams and colleagues describing a new panel for the diagnosis of liver fibrosis in chronic hepatitis C (1). Before this panel can be considered valid and put to routine use, several steps need to be taken. 1) As discussed by the authors, the sample size is particularly small for the cirrhosis stage. The estimates and comparisons of AUROCs with less than 20 patients are misleading (Figure 1). 2) Pre-analytical and analytical studies are mandatory before a panel can be widely recommended. The storage of serum at -20° C affects the concentrations of the components, and curiously an analytical study of FibroTest assessing this variability was not mentioned (2). 3) The methodology should take into account the risk of failure of liver biopsy as well as the risk of failure of the biochemical components. Discordant results must be discussed case by case to find the cause of discordance. This is particularly important in their population, as the median length of liver biopsies is small (13 mm). The details of discordant cases (between biopsy and biomarkers) should be given with the potential cause of the false positivesand negative, as well as the independent criteria of diagnosis, such as varices, prothrombin time, platelets, and ultrasound. This methodology has been described in Clin Chem for FibroTest validation (3). 4) More studies concerning patients at risk of false positives or false negatives should be performed before this test can be widely recommended, including those with Gilbert’s syndrome, arthrosis and renal insufficiency. Hyaluronic acid has a high risk of false positive, particularly in the aged population with arthrosis. 5) Several comments concerning the FibroTest are not accurate. Since the first publication, several publications including independent prospective studies have demonstrated the validity of this test: Callewert et al (4) versus glycomics, Castera et al versus elastometry (5), Halfon et al (6) and Sebastiani et al (7). Contrary to the author’s statement, the details of FibroTest-ActiTest predictive values were given in detail in an overview published in 2004 (8). Also, contrary to the author’s statement, the FibroTest diagnostic value is similar for all stages without an indeterminate zone (8), with a percentage of failure due to the FibroTest significantly lower than that of liver biopsy (8). 6) Several advantages of FibroTest were also omitted in the discussion. As with the development of drugs, an industrial biomarker requires a research and development program, including an assessment of all the risks of variability and false positives and false negatives. Contrary to many other tests, FibroTest has been professionally developed and includes pre-analytical and analytical recommendations and security algorithms. Notably, the conditions used by some of the present authors (9) in their first study of the FibroTest did not follow the recommendations. An electronic letter concerning this point has been published and should have been mentioned (10). The authors also did not mention that several direct comparisons have observed significantly higher diagnostic values of FibroTest versus APRI, age platelets ratio and the Forn’s index (8). 7) FibroTest results are given together with ActiTest, a validated method of scoring the necrotico-inflammatory features, which is also an advantage for clinicians (8). Finally, biomarkers should not be limited to a simple formula but instead require true development to reduce pre-analytical and analytical variability and to evaluate their clinical benefit. Cumulative and centralized data are particularly useful in order to develop security algorithms, reducing the risks of false positives and false negatives. References 1. Adams LA, Bulsara M, Rossi E, Deboer B, Speers D, George J, Kench J, Farrell G, McCaughan GW, Jeffrey GP. Hepascore: An Accurate Validated Predictor of Liver Fibrosis in Chronic Hepatitis C Infection. Clin Chem. 2005 Jul 28; 2. Imbert-Bismut F, Messous D, Thibaut V, Myers RB, Piton A, Thabut D, Devers L, Hainque B, Mercadier A, Poynard T. Intralaboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab Med 2004;42:323-333. 3. Poynard T, Munteanu M, Imbert-Bismut F, Charlotte F, Thabut D, Le Calvez S, Messous D, Thibault V, Benhamou Y, Moussalli J, Ratziu V. Prospective Analysis of Discordant Results between Biochemical Markers and Biopsy in Patients with Chronic Hepatitis C. Clin Chem. 2004;50:1344-1355.
4. Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nature Med 2004;10;429-34.
7. Sebastiani G, Vario A, Boccato S, Ferrari A, Pistis R, Benvegnù L, Alberti A. Predictive Value of Three Non-Invasive Methods For Assessing Liver Fibrosis In Chronic Hepatitis C. Hepatology 2004.40; 4: 280A
(Abstract)
8. Poynard T, Imbert-Bismut F, Munteanu M, Messous D, Myers RP, Thabut D, Ratziu V, Mercadier A, Benhamou Y, Hainque B. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV-Fibrosure)
and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol 2004;3:8.
9. Rossi E, Adams L, Prins A, Bulsara M, De Boer B, Garas G, MacQuillan G, Speers D, Jeffrey G. Validation of the FibroTest Biochemical Markers Score in Assessing Liver Fibrosis in Hepatitis C Patients. Clin Chem.
2003;49:450-454.
10. Poynard T, Imbert-Bismut F, Ratziu V, Myers RP, Di Martino V, Thabut D, Moussalli J, Benhamou Y. Fibrotest even better than liver biopsy? Clin Chem 2003. Electronic letter
http://www.clinchem.org/cgi/eletters/49/3/450. Response: (21 March 2003) |
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