Combination of Blood Tests for Significant Fibrosis and Cirrhosis Improves the Assessment of Liver-Prognosis in Chronic Hepatitis C

J. Boursier; C. Brochard; S. Bertrais; S. Michalak; Y. Gallois; I. Fouchard-Hubert; F. Oberti; M.-C. Rousselet; P. Calès


Aliment Pharmacol Ther. 2014;40(2):178-188. 

In This Article

Abstract and Introduction


Background Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross-sectional studies have shown their combination significantly improves diagnostic accuracy.

Aim To compare the prognostic accuracy of six blood fibrosis tests and liver biopsy, and evaluate if test combination improves the liver-prognosis assessment in chronic hepatitis C (CHC).

Methods A total of 373 patients with compensated CHC, liver biopsy (Metavir F) and blood tests targeting fibrosis (APRI, FIB4, Fibrotest, Hepascore, FibroMeter) or cirrhosis (CirrhoMeter) were included. Significant liver-related events (SLRE) and liver-related deaths were recorded during follow-up (started the day of biopsy).

Results During the median follow-up of 9.5 years (3508 person-years), 47 patients had a SLRE and 23 patients died from liver-related causes. For the prediction of first SLRE, most blood tests allowed higher prognostication than Metavir F [Harrell C-index: 0.811 (95% CI: 0.751–0.868)] with a significant increase for FIB4: 0.879 [0.832–0.919] (P = 0.002), FibroMeter: 0.870 [0.812–0.922] (P = 0.005) and APRI: 0.861 [0.813–0.902] (P = 0.039). Multivariate analysis identified FibroMeter, CirrhoMeter and sustained viral response as independent predictors of first SLRE. CirrhoMeter was the only independent predictor of liver-related death. The combination of FibroMeter and CirrhoMeter classifications into a new FM/CM classification improved the liver-prognosis assessment compared to Metavir F staging or single tests by identifying five subgroups of patients with significantly different prognoses.

Conclusions Some blood fibrosis tests are more accurate than liver biopsy for determining liver prognosis in CHC. A new combination of two complementary blood tests, one targeted for fibrosis and the other for cirrhosis, optimises assessment of liver-prognosis.


The dramatic progress in chronic hepatitis C (CHC) therapy let appear the exciting possibility to cure almost patients because of the high rate of sustained viral response (SVR) and little side effects. As a consequence, determination of fibrosis stage in CHC could appear soon obsolete as it will have much less influence in the treatment decision. Nevertheless, such therapies are not yet available in clinical practice. In addition, for economic reasons, several countries will probably continue to select patients for treatment according to their liver-related prognosis that is mainly related to liver fibrosis degree. Finally, cirrhosis will remain an important diagnosis because it is associated with lower rates of SVR with the new therapies and, even if the virus is eradicated, the screening for hepatocellular carcinoma is still required as cirrhosis might not reverse after SVR. For all these reasons, liver fibrosis evaluation is still relevant in CHC patients.

Compared to staging on liver biopsy, blood fibrosis tests have several advantages for the evaluation of liver fibrosis: they are noninvasive, they can be performed anywhere, there is no measurement failure and their reproducibility is excellent.[1] As a rule, blood fibrosis tests have been constructed for the binary diagnosis of significant fibrosis, i.e. Metavir F0/1 vs. F ≥ 2. Because their results are well correlated with the ordinal scale of pathological fibrosis stages, some fibrosis classifications have been then developed to provide an estimation of the fibrosis stage(s) from the blood test result. These fibrosis classifications are particularly helpful for physicians in clinical practice: they give an interpretation of blood test result, they provide a more precise diagnosis of liver fibrosis than the initially proposed binary diagnosis of significant fibrosis and, as fibrosis staging on liver biopsy, they discriminate the patients into several subgroups supposed to have different levels of liver fibrosis.

Nevertheless, the use of blood fibrosis tests in clinical practice remains under debate.[2,3] Cross-sectional studies that demonstrated the good accuracy of blood fibrosis tests are criticised because they used liver biopsy as reference and were thus impaired by the lack of a perfect gold standard.[4] Moreover, the fibrosis classifications may be considered imprecise when their diagnosis is 'Metavir F1/2' or 'F3/4'. Keeping in mind that the main interest of liver fibrosis assessment in CHC is to evaluate prognosis, the best way to circumvent these drawbacks and assess the practical relevance of blood fibrosis tests is to evaluate their prognostic significance in longitudinal studies. Previous studies that evaluated the prognostic value of blood fibrosis tests shared several drawbacks: small samples of patients,[5,6] heterogeneous cohorts with various causes of chronic liver diseases,[7] relatively short follow-up,[8–10] primary outcome focusing on mortality rather than liver decompensation,[6,9,10] and no direct comparison between blood fibrosis tests.[5,7,8,10] Finally, these studies evaluated the prognostic value of single blood fibrosis tests.

Consequently, the primary aim of the present study was to compare the prognostic accuracy of several blood fibrosis tests and liver biopsy for the prediction of liver-related events in a large cohort of CHC patients with long-term follow-up. As recent studies demonstrated that combination of fibrosis tests significantly improves the diagnostic accuracy,[11–13] our secondary aim was to evaluate if a combination of blood fibrosis tests can also improve the liver-prognosis assessment.