The first main finding of our study is the absence of significant differences between the diagnostic values of FibroTest, FibrometerA, and Hepascore in patients with ALD, both for the diagnosis of advanced fibrosis and for the diagnosis of cirrhosis. FibroTest had the best independent diagnostic value in multivariate analysis, and adding FibrometerA or Hepascore to FibroTest did not significantly improve the AUROC. Combinations marginally improved the predictive values of these tests alone.
The second main finding was that biomarkers had similar prognostic values as biopsy, the classical gold standard, at 5-year and 10-year follow-ups. FibroTest had the best prognostic value in multivariate analysis, without clinically significant improvement when combined with the other biomarkers.
Our results were similar to previous direct comparisons in patients with hepatitis C, in which no significant differences between these patented biomarkers were found.33, 34
Indirect comparisons between sensitivities, specificities, AUROC and predictive values are hazardous due to variability factors, the two most important being the prevalences of stages defining advanced and nonadvanced fibrosis and the biopsy length (28, 29).
The prevalence of each fibrosis stage according to the METAVIR scoring system was different between our study and Calés' study11: F0 = 7%, F1 = 30%, F2 = 22%, F3 = 10%, F4 = 31%; and F0 = 13%, F1 = 18%, F2 = 17%, F3 = 12%, F4 = 41%, respectively. The difference between the mean fibrosis values of advanced fibrosis minus the fibrosis stage of nonadvanced fibrosis (DANA) was 2.33 in the present study and 2.76 in the study by Calés.12 Poynard et al. recently showed the major impact of the DANA in the variability of the observed AUROC.28 The observed AUROC of FibroTest was 0.83 in the present study, equivalent to 0.86 after standardization using a DANA of 2.5 (same prevalence for all fibrosis stages), and 0.96 before and 0.93 after standardization in they study by Calés. When standardized, the difference between AUROC was 0.07 not 0.13.
One advantage of liver biopsy versus specific markers of fibrosis is the ability to diagnose alcoholic hepatitis, enabling patients to receive corticosteroid therapy. One advantage of FibroTest versus the other markers is that it has been validated together with AshTest, a patented specific biomarker of severe alcoholic hepatitis. In the present study presumed alcoholic hepatitis using AshTest had the same significant prognostic value as biopsy. This prognostic value was not found in multivariate analysis, but this was expected as all patients had been treated with corticosteroids, which had a significant impact on survival.33
When we compared the diagnostic value of the three patented biomarkers in the same patients, their diagnostic performances were quite similar. However, in logistic regression including the three scores, FibroTest was the only score to be associated independently with significant fibrosis. The absence of statistical independence of Hepascore can be explained by the fact that this score shares several parameters with FibroTest and FibrometerA.
The diagnostic value of FibroTest and FibrometerA for the diagnosis of alcoholic cirrhosis was almost perfect, with AUROC reaching 0.94.
It is not surprising, therefore, that diagnostic performances of scores combining biomarkers were not better than FibroTest used alone. Because liver biopsy is an imperfect gold standard, it is very difficult to speculate about predictive values, as it is possible that false negatives/positives of biomarkers could actually be false negatives/positives of liver biopsy. The best combination was FibroTest ≥0.70 and PI <70%. If the biopsy was always accurate, the diagnosis of significant fibrosis could be made with 100% certainty and the diagnosis of cirrhosis with 89% certainty when FibroTest was ≥0.70 and PI <70%.
Combinations did not improve negative predictive values, and FibroTest used alone had the best negative predictive value. Again, if biopsy was always accurate, cirrhosis could be ruled out with 100% certainty when FibroTest was lower than 0.30. This situation was observed in 35% of included patients.
FibroTest, FibrometerA, and Hepascore had significantly higher diagnostic values than the nonpatented scores, APRI, Forns, and Fib4. Greater accuracy of FibroTest compared to APRI and Forns has already been observed in patients with chronic hepatitis C and mixed liver diseases.36–38 In patients with ALD, AST/ALT ratio were different than in HCV patients, platelets can decrease according to alcohol consumption whatever the fibrosis stage, and GGT values decrease in patients with severe cirrhosis.39 It is important that these validated patented tests are covered by healthcare insurance programs.
This study has shown that FibroTest, when used in patients with chronic ALD, can predict liver-related mortality at least as well as liver biopsy stage, as has already been observed in patients with chronic hepatitis C12 and B.13 The prognostic values of FibroTest, FibrometerA, Hepascore, and biopsy were similar and better than the Pugh prognostic score and those of the nonpatented scores.
These results confirm a posteriori that these markers have at baseline a high value for the diagnosis of advanced fibrosis. Liver biopsy is not a perfect gold standard and the diagnostic studies of fibrosis markers must take into account all the factors associated with the risk of biopsy failure. Because biomarkers and biopsy similarly predict survival, biomarkers seem to have the same rate of error as liver biopsy for baseline diagnosis.
The presence of baseline histologic signs of acute alcoholic hepatitis was not an independent prognostic factor. Similarly the AshTest, a validated biomarker of severe acute alcoholic hepatitis, also was not associated independently with liver disease mortality. Further studies with more patients and longer follow-up are needed to exclude the prognostic value of histologic or biologic alcoholic hepatitis independent of fibrosis, as these two liver injuries are highly associated.
Another finding of this study was that it showed that FibroTest, FibrometerA, and biopsy fibrosis staging also were useful in determining overall survival; their prognostic values were not unexpectedly, however, better for survival or nonliver-related death; this result was expected according to the numerous nonliver-related causes of death attributable to excessive alcohol consumption.
In patients with alcoholic liver disease, FibrometerA or Hepascore do not have better diagnostic or prognostic performances than FibroTest alone, or than combinations between these biomarkers. In multivariate analyses FibroTest was the most informative biomarker. As in patients with chronic viral hepatitis C and B, the prognostic value of FibroTest was similar to that of biopsy.