Blood Tests for Assessment of Liver-prognosis in Hepatitis C
Blood Tests for Assessment of Liver-prognosis in Hepatitis C
Currently, the use of blood fibrosis tests for the evaluation of fibrosis in CHC patients remains controversial. This is due to the reported moderate accuracy of blood fibrosis tests for the diagnosis of intermediate stages of fibrosis, and the lack of perfect gold standard in the cross-sectional studies that evaluated their diagnostic accuracy. Basically, a more comprehensive approach to validate the use of blood fibrosis test in clinical practice is the evaluation of their prognostic accuracy for clinical events in longitudinal studies. We focused the current work on this approach, and our study has several strengths: (i) a large number of patients included, (ii) only a single cause of chronic liver disease: CHC, (iii) a well-balanced repartition of fibrosis stages as described in a large reference cohort of CHC patients, (iv) two clinically relevant outcomes evaluated: SLRE (for which prediction by blood fibrosis tests is poorly evaluated in the literature) and liver-related death, (v) long-term follow-up (median: 9.5 years) and (vi) direct comparison of liver biopsy with six blood fibrosis tests including a new test specifically developed for cirrhosis.
One of the 13 F0 patients included in our study had jaundice after 5.5 years of follow-up. This surprising evolution may be explained by the conjunction of two drawbacks of fibrosis staging on liver biopsy: underestimation of liver fibrosis at inclusion because of sample bias and rapid progression of fibrosis during follow-up than cannot be closely follow by repeated liver biopsy. Our study also demonstrates the poor discriminative ability of intermediate pathological fibrosis stages for the medium-term prediction of liver prognosis. Indeed, despite the good discriminative ability of Metavir F staging according to the Harrell C-index, the cumulative incidence of first SLRE and survival without liver-related death were not different among F0 to F3 stages in our population, and only F4 patients had a significantly worse prognosis. This result is in accordance with those obtained in the HALT-C cohort where incidence of liver-related outcomes was significantly higher in Ishak F6 stage vs. F5 and in F5 vs. F4, but not in F4 vs. F3.
Our results demonstrate that blood fibrosis tests are globally at least as accurate as Metavir F staging for the prediction of liver prognosis in CHC patients. Indeed, none of the blood fibrosis tests had a significantly lower Harrell C-index than liver biopsy for the prediction of SLRE or liver-related death. In multivariate analyses including each blood test with Metavir F staging, almost all blood fibrosis tests were independent predictors of SLRE or liver-related death, suggesting that blood fibrosis tests provide relevant prognostic information. Moreover, FibroMeter and CirrhoMeter were independent predictors of SLRE with no role for Metavir F, as was CirrhoMeter for liver-related death.
Among the six blood fibrosis tests evaluated, multivariate analysis identified FibroMeter and CirrhoMeter as the best combination for the prediction of first SLRE. These two tests, the former specifically targeted for significant fibrosis and the latter for cirrhosis, are very complementary (Figure 2) and their association improves the prediction of first SLRE: FibroMeter is more predictive at low fibrosis levels and CirrhoMeter at high fibrosis levels since it amplifies the test scale like a two-speed gearbox. Finally, similar to the Child–Pugh score or hepatic venous pressure gradient measurement in cirrhotic patients, CirrhoMeter can stratify high FibroMeter values to improve the identification of subgroups with significantly different prognoses. Because it requires a very large population to robustly determine a posteriori prognostic subgroups, we decided to stratify patients according to the a priori fibrosis classifications or diagnostic cut-offs that are currently used in clinical practice. In this setting, the combination of FibroMeter and CirrhoMeter fibrosis classifications in the FM/CM classification has several advantages compared to Metavir F staging. First, whereas Metavir F staging identified only two groups of patients with different prognoses (F0–3 vs. F4), FM/CM classification identified five significantly different groups (Figure 3a). Second, contrary to Metavir F staging, no SLRE occurred in the lower class of FM/CM classification, defining thus a subgroup with excellent prognosis. Third, the highest class of FM/CM identified a subgroup of very high-risk patients that was not identified by Metavir F staging.
FIB4, an inexpensive and easy-to-calculate blood fibrosis test, showed very good prognostic accuracy in our study. It was not selected as an independent predictor of first SLRE by multivariate analysis, probably because it was masked by the high complementary role of FibroMeter and CirrhoMeter for this endpoint. By using its two recommended diagnostic cut-offs, FIB4 identified three subgroups of patients whose prognosis was significantly different. However, 11 patients from the best-prognosis subgroup experienced SLRE during their follow-up whereas, by comparison, no patients included in the first class of FibroMeter or CirrhoMeter classification had SLRE. This could be due to an inadequate choice for FIB4 thresholds. Indeed, no SLRE occurred during follow-up of patients included in the first three deciles of FIB4 (see Figure S5a). This suggests that FIB4 is also able to determine a subgroup of patients with excellent prognosis, and FIB4 thresholds should be refined for this purpose.
(Enlarge Image)
Figure S5.
Cumulative incidence of first significant liver-related event as a function of deciles of FIB4 (a), FibroMeter (b), CirrhoMeter (c), Fibrotest (d), Hepascore (e), or APRI (f)
Two recent studies have suggested that annual surveillance by a noninvasive test of liver fibrosis is cost effective compared to the current surveillance with liver biopsy in CHC patients. As our study results but using a different approach, these works provide arguments in favour of noninvasive testing instead of liver biopsy in clinical practice. We may suppose that fibrosis tests with the best prognostic accuracy will be the most cost effective. Furthermore, the FM/CM classification has the advantage of using two tests (FibroMeter and CirrhoMeter) which are simultaneously calculated with no additional costs because they include the same markers but with different coefficients. To our knowledge, published cost-effectiveness studies have evaluated only a single noninvasive test (Fibrotest or Fibroscan) against liver biopsy, and none has yet compared different noninvasive tests between them. Such article will help to define the best strategy for clinical practice, and if a strategy that uses the FM/CM classification dominates the others.
Results from the present study were obtained in a single-centre population of CHC patients and should be independently validated in a large multicenter cohort. In addition, our study has two main limitations. The first is the lack of elastometry evaluation. Indeed, as for blood fibrosis tests, liver stiffness measured by Fibroscan appears to be a prognostic factor in CHC patients. However, Fibroscan became available in 2004 and thus most of our patients had no liver stiffness measurement at the time of their inclusion. The second limitation is the absence of repeated measurements for blood fibrosis tests during follow-up. Noninvasive tests of fibrosis can be easily repeated but the prognostic significance of their evolution during patient follow-up remains poorly evaluated. In the upcoming area of new anti-viral treatments, evaluation of fibrosis and even more cirrhosis regression will be particularly relevant in patients who will achieve SVR.
In conclusion, blood fibrosis tests are also prognostic tests at least as accurate as liver biopsy for the prediction of liver prognosis in patients with CHC. A combination of two complementary blood tests, one targeted for fibrosis (FibroMeter) and the other for cirrhosis (CirrhoMeter), is more accurate than liver biopsy and appears as a simple and accurate method for the baseline assessment of prognosis in clinical practice.
Discussion
Currently, the use of blood fibrosis tests for the evaluation of fibrosis in CHC patients remains controversial. This is due to the reported moderate accuracy of blood fibrosis tests for the diagnosis of intermediate stages of fibrosis, and the lack of perfect gold standard in the cross-sectional studies that evaluated their diagnostic accuracy. Basically, a more comprehensive approach to validate the use of blood fibrosis test in clinical practice is the evaluation of their prognostic accuracy for clinical events in longitudinal studies. We focused the current work on this approach, and our study has several strengths: (i) a large number of patients included, (ii) only a single cause of chronic liver disease: CHC, (iii) a well-balanced repartition of fibrosis stages as described in a large reference cohort of CHC patients, (iv) two clinically relevant outcomes evaluated: SLRE (for which prediction by blood fibrosis tests is poorly evaluated in the literature) and liver-related death, (v) long-term follow-up (median: 9.5 years) and (vi) direct comparison of liver biopsy with six blood fibrosis tests including a new test specifically developed for cirrhosis.
One of the 13 F0 patients included in our study had jaundice after 5.5 years of follow-up. This surprising evolution may be explained by the conjunction of two drawbacks of fibrosis staging on liver biopsy: underestimation of liver fibrosis at inclusion because of sample bias and rapid progression of fibrosis during follow-up than cannot be closely follow by repeated liver biopsy. Our study also demonstrates the poor discriminative ability of intermediate pathological fibrosis stages for the medium-term prediction of liver prognosis. Indeed, despite the good discriminative ability of Metavir F staging according to the Harrell C-index, the cumulative incidence of first SLRE and survival without liver-related death were not different among F0 to F3 stages in our population, and only F4 patients had a significantly worse prognosis. This result is in accordance with those obtained in the HALT-C cohort where incidence of liver-related outcomes was significantly higher in Ishak F6 stage vs. F5 and in F5 vs. F4, but not in F4 vs. F3.
Our results demonstrate that blood fibrosis tests are globally at least as accurate as Metavir F staging for the prediction of liver prognosis in CHC patients. Indeed, none of the blood fibrosis tests had a significantly lower Harrell C-index than liver biopsy for the prediction of SLRE or liver-related death. In multivariate analyses including each blood test with Metavir F staging, almost all blood fibrosis tests were independent predictors of SLRE or liver-related death, suggesting that blood fibrosis tests provide relevant prognostic information. Moreover, FibroMeter and CirrhoMeter were independent predictors of SLRE with no role for Metavir F, as was CirrhoMeter for liver-related death.
Among the six blood fibrosis tests evaluated, multivariate analysis identified FibroMeter and CirrhoMeter as the best combination for the prediction of first SLRE. These two tests, the former specifically targeted for significant fibrosis and the latter for cirrhosis, are very complementary (Figure 2) and their association improves the prediction of first SLRE: FibroMeter is more predictive at low fibrosis levels and CirrhoMeter at high fibrosis levels since it amplifies the test scale like a two-speed gearbox. Finally, similar to the Child–Pugh score or hepatic venous pressure gradient measurement in cirrhotic patients, CirrhoMeter can stratify high FibroMeter values to improve the identification of subgroups with significantly different prognoses. Because it requires a very large population to robustly determine a posteriori prognostic subgroups, we decided to stratify patients according to the a priori fibrosis classifications or diagnostic cut-offs that are currently used in clinical practice. In this setting, the combination of FibroMeter and CirrhoMeter fibrosis classifications in the FM/CM classification has several advantages compared to Metavir F staging. First, whereas Metavir F staging identified only two groups of patients with different prognoses (F0–3 vs. F4), FM/CM classification identified five significantly different groups (Figure 3a). Second, contrary to Metavir F staging, no SLRE occurred in the lower class of FM/CM classification, defining thus a subgroup with excellent prognosis. Third, the highest class of FM/CM identified a subgroup of very high-risk patients that was not identified by Metavir F staging.
FIB4, an inexpensive and easy-to-calculate blood fibrosis test, showed very good prognostic accuracy in our study. It was not selected as an independent predictor of first SLRE by multivariate analysis, probably because it was masked by the high complementary role of FibroMeter and CirrhoMeter for this endpoint. By using its two recommended diagnostic cut-offs, FIB4 identified three subgroups of patients whose prognosis was significantly different. However, 11 patients from the best-prognosis subgroup experienced SLRE during their follow-up whereas, by comparison, no patients included in the first class of FibroMeter or CirrhoMeter classification had SLRE. This could be due to an inadequate choice for FIB4 thresholds. Indeed, no SLRE occurred during follow-up of patients included in the first three deciles of FIB4 (see Figure S5a). This suggests that FIB4 is also able to determine a subgroup of patients with excellent prognosis, and FIB4 thresholds should be refined for this purpose.
(Enlarge Image)
Figure S5.
Cumulative incidence of first significant liver-related event as a function of deciles of FIB4 (a), FibroMeter (b), CirrhoMeter (c), Fibrotest (d), Hepascore (e), or APRI (f)
Two recent studies have suggested that annual surveillance by a noninvasive test of liver fibrosis is cost effective compared to the current surveillance with liver biopsy in CHC patients. As our study results but using a different approach, these works provide arguments in favour of noninvasive testing instead of liver biopsy in clinical practice. We may suppose that fibrosis tests with the best prognostic accuracy will be the most cost effective. Furthermore, the FM/CM classification has the advantage of using two tests (FibroMeter and CirrhoMeter) which are simultaneously calculated with no additional costs because they include the same markers but with different coefficients. To our knowledge, published cost-effectiveness studies have evaluated only a single noninvasive test (Fibrotest or Fibroscan) against liver biopsy, and none has yet compared different noninvasive tests between them. Such article will help to define the best strategy for clinical practice, and if a strategy that uses the FM/CM classification dominates the others.
Results from the present study were obtained in a single-centre population of CHC patients and should be independently validated in a large multicenter cohort. In addition, our study has two main limitations. The first is the lack of elastometry evaluation. Indeed, as for blood fibrosis tests, liver stiffness measured by Fibroscan appears to be a prognostic factor in CHC patients. However, Fibroscan became available in 2004 and thus most of our patients had no liver stiffness measurement at the time of their inclusion. The second limitation is the absence of repeated measurements for blood fibrosis tests during follow-up. Noninvasive tests of fibrosis can be easily repeated but the prognostic significance of their evolution during patient follow-up remains poorly evaluated. In the upcoming area of new anti-viral treatments, evaluation of fibrosis and even more cirrhosis regression will be particularly relevant in patients who will achieve SVR.
In conclusion, blood fibrosis tests are also prognostic tests at least as accurate as liver biopsy for the prediction of liver prognosis in patients with CHC. A combination of two complementary blood tests, one targeted for fibrosis (FibroMeter) and the other for cirrhosis (CirrhoMeter), is more accurate than liver biopsy and appears as a simple and accurate method for the baseline assessment of prognosis in clinical practice.
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