Clinical applicability of non-invasive markers for liver fibrosis in chronic hepatitis C
Authors: Vincent Leroy, Jean-Pierre Zarski
Journal: Journal of Hepatology (2008)

We fully agree with Sebastiani et al. [[1]Sebastiani G. Alberti A. Implementing non-invasive markers for liver fibrosis in clinical practice.J Hepatol. 2008; 48: 880-881Abstract Full Text Full Text PDF Scopus (5) Google Scholar] regarding the need for a rational approach to implementing non-invasive tests of liver fibrosis in clinical practice. We recently showed that available biological tests, from the simplest APRI to the most sophisticated Fibrotest or Fibrometer, had global diagnostic performances similar to each other with AUROC around 0.80 for the diagnosis of significant fibrosis [[2]Leroy V. Hilleret M.N. Sturm N. Trocme C. Renversez J.C. Faure P. et al.Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C.J Hepatol. 2007; 46: 775-782Google Scholar]. These tests are clearly not accurate enough to precisely stage liver fibrosis in all cases [[3]Parkes J. Guha I.N. Roderick P. Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C.J Hepatol. 2006; 44: 462-474Google Scholar]. However, they may give important clues on fibrosis especially when used in combination. Two algorithms have been recently proposed by Sebastiani et al. [[4]Sebastiani G. Vario A. Guido M. Noventa F. Plebani M. Pistis R. et al.Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C.J Hepatol. 2006; 44: 686-693Google Scholar] and by our team [[2]Leroy V. Hilleret M.N. Sturm N. Trocme C. Renversez J.C. Faure P. et al.Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C.J Hepatol. 2007; 46: 775-782Google Scholar] in order to reliably assess fibrosis stages without the need for a liver biopsy. Interestingly, both algorithms combine the same tests, namely, APRI and Fibrotest, which have been found to be statistically independent. In the study presented here, Sebastiani et al. [[1]Sebastiani G. Alberti A. Implementing non-invasive markers for liver fibrosis in clinical practice.J Hepatol. 2008; 48: 880-881Abstract Full Text Full Text PDF Scopus (5) Google Scholar] compared the performance of these algorithms and found that both attained very good accuracy, with a greater reduction of liver biopsies by using their algorithm. These important results give rise to several comments. Sebastiani’s algorithm is sequential and utilises as first-line assessment the cost free APRI. Such a sequential approach is pragmatic since this test is virtually always available at the time patients are referred for chronic hepatitis C. At this stage physicians must be aware that this test can be coupled with simple laboratory tests that perform well in terms of fibrosis prediction, as recently reported by Nahon et al. [[5]Nahon P. Thabut G. Ziol M. Htar M.T. Cesaro F. Barget N. et al.Liver stiffness measurement versus clinicians’ prediction or both for the assessment of liver fibrosis in patients with chronic hepatitis C.Am J Gastroenterol. 2006; 101: 2744-2751Google Scholar]. At this step the first clinical question asked by both algorithms is can one exclude significant fibrosis?, i.e. fibrosis stage greater than F1. This question is crucial since patients with no or mild fibrosis must be reasssured and antiviral treatment can be delayed. At this stage, underestimation of liver fibrosis may have a strong detrimental impact on clinical management and the use of non-invasive tests with excellent negative predictive value (NPV) is mandatory. In Sebastiani’s algorithm this difficulty is overcome by performing a liver biopsy in all patients with APRI below 0.5 and in patients with APRI ranging from 0.5 to 1.5 and Fibrotest lower than 0.32. In our published series of 188 patients in which the percentage of F0-F1 stages was higher than that of Sebastiani’s (49% versus 30%), these criteria were met in 51% of patients. These data mean that by using Sebastiani’s algorithm a substantial number of biopsies would be performed in patients with the less severe fibrosis stage. In our algorithm, the use of more stringent cut-offs (APRI < 0.5 and Fibrotest < 0.22) allowed to select a small proportion (13%) of patients in whom significant fibrosis could be excluded with more than 90% certainty. Such accuracy seems to us reasonable to wave liver biopsy in this situation, especially when the clinical setting is consistent with a mild disease. Following Sebastiani’s algorithm, patients with APRI greater than 1.5 or with APRI ranging from 0.5 to 1.5 and Fibrotest > 0.32 are expected to have significant fibrosis with an excellent positive predictive value (PPV). In our series, we confirmed these results although the PPV was slightly lower (76%) due again to the lower prevalence of stages F2-F3-F4 in our population. We agree that such accuracy is sufficient to make the decision to initiate antiviral therapy at least in naïve patients without severe comorbidities. However, a major clinical question remains to be answered at this step, which is can one exclude the presence of cirrhosis? This point is also crucial since cirrhotic patients must have specific management including screening for liver failure, portal hypertension and hepatocellular carcinoma. For these reasons, Sebastiani et al. [[4]Sebastiani G. Vario A. Guido M. Noventa F. Plebani M. Pistis R. et al.Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C.J Hepatol. 2006; 44: 686-693Google Scholar] described a second algorithm for the diagnosis of cirrhosis that logically should be applied to all patients classified as having significant fibrosis. In this algorithm, patients with APRI greater than 0.5 and Fibrotest F2-F3 should proceed to undergoing a liver biopsy. In our series, applying sequentially both Sebastiani’s algorithms the liver biopsy would have been eventually avoided in only 11% of patients. In our algorithm, we have chosen stringent cut-offs for APRI (2.0) and Fibrotest (0.59) that allowed the diagnosis of extensive fibrosis in 20% of patients with excellent PPV (superior to 93%). Other tools such as ultrasound could also help in the diagnosis of cirrhosis [[6]Aube C. Oberti F. Korali N. Namour M.A. Loisel D. Tanguy J.Y. et al.Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis.J Hepatol. 1999; 30: 472-478Google Scholar]. In our algorithm, patients in the grey zone in whom neither F0-F1 nor F3-F4 can be affirmed are offered a liver biopsy. As highlighted by Sebastiani et al. [[1]Sebastiani G. Alberti A. Implementing non-invasive markers for liver fibrosis in clinical practice.J Hepatol. 2008; 48: 880-881Abstract Full Text Full Text PDF Scopus (5) Google Scholar] these criteria are met by the majority (67% in our study) of patients, explaining the low number of avoided biopsies in our algorithm. Another option would be to choose other cut-offs in order to accurately exclude cirrhosis in patients suspected of having significant fibrosis. We thus performed a new statistical analysis showing that cirrhosis could be ruled out in patients with APRI < 1.5 and FT < 0.46 with 100% certainty, such a situation being met in 59% of patients. In this setting, other non-invasive tests such as Fibrometer and Fibroscan appear to be also very accurate to exclude cirrhosis [7Cales P. Oberti F. Michalak S. Hubert-Fouchard I. Rousselet M.C. Konate A. et al.A novel panel of blood markers to assess the degree of liver fibrosis.Hepatology. 2005; 42: 1373-1381Google Scholar, 8Ganne-Carrie N. Ziol M. de Ledinghen V. Douvin C. Marcellin P. Castera L. et al.Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.Hepatology. 2006; 44: 1511-1517Google Scholar]. In this situation, non-invasive tests allow the selection of patients at high risk of significant fibrosis but without cirrhosis, who can be eligible for antiviral treatment even without an accurate knowledge of the stage of fibrosis (Fig. 1 ). In conclusion, we fully agree with Sebastiani et al. regarding the respective role of non-invasive tests and liver biopsy. Non-invasive tests should not be considered as tools aiming at substituting liver biopsy – they do not give the same information – but in some cases they may render the biopsy unnecessary to make the right clinical decision. An increasing number of non-invasive tests and algorithms are becoming available. As we are awaiting further studies that will compare these tests in the future, we present here a pragmatic attitude that seems to us rational and applicable in daily clinical practice.