FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest†
Article first published online: 13 JUN 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 46, Issue 1, pages 32–36, July 2007
How to Cite
Vallet-Pichard, A., Mallet, V., Nalpas, B., Verkarre, V., Nalpas, A., Dhalluin-Venier, V., Fontaine, H. and Pol, S. (2007), FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology, 46: 32–36. doi: 10.1002/hep.21669
Potential conflict of interest: Nothing to report.
- Issue published online: 27 JUN 2007
- Article first published online: 13 JUN 2007
- Manuscript Accepted: 9 JAN 2007
- Manuscript Received: 9 OCT 2006
To optimize the management of patients with chronic hepatitis C virus (HCV) infection, noninvasive tests to determine the degree of hepatic fibrosis have been developed. The aims of this study were (1) to validate a simple, inexpensive, noninvasive test called FIB-4, which combines standard biochemical values (platelets, ALT, AST) and age, in a series of 847 liver biopsies performed in HCV-monoinfected patients; and (2) to compare the results of 780 FIB-4 and FibroTests performed the same day in a series of 592 HCV-infected patients. The FIB-4 index enabled the correct identification of patients with severe fibrosis (F3-F4) and cirrhosis with an area under the receiver operating characteristic curve of 0.85 (95% CI 0.82-0.89) and 0.91 (95% CI 0.86-0.93), respectively. An FIB-4 index <1.45 had a negative predictive value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. An FIB-4 index higher than 3.25 had a positive predictive value to confirm the existence of a significant fibrosis (F3-F4) of 82.1% with a specificity of 98.2%. Using these ranges, 72.8% of the 847 liver biopsies were correctly classified. The FIB-4 index was strongly correlated to the FibroTest results for a score <1.45 or >3.25 (κ = 0.561, P < 0.01). A FIB-4 value <1.45 or >3.25 (64.6% of the cases) was concordant with FibroTest results in 92.1% and 76%, respectively. Conclusion: For values outside 1.45-3.25, the FIB-4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results. (HEPATOLOGY 2007.)
The accurate evaluation of liver fibrosis in chronic hepatitis C is mandatory to appraise therapeutic indications and prognosis, because complications mainly occur in patients in advanced stages of their disease. The gold standard for assessing hepatic fibrosis is liver histology. Liver biopsy (LB) is however limited by its invasive nature1–3; poor acceptance, especially when repeated measures are required; availability and cost, particularly in non-Western countries; intra- and interobserver variability4, 5; and sampling errors, which produce approximately 24% of false negatives for cirrhosis.6, 7
Consequently, noninvasive tests to assess hepatic fibrosis have been developed, such the AST-to-platelet ratio index (APRI),8 the Forns test,9 and FibroTest (Biopredictive SAS, Paris, France),10–16 which combine several biochemical parameters. More recently, transient elastography (FibroScan, Echosens, Paris, France)—a morphological method that measures liver stiffness— has been evaluated.17 Other biochemical tests such as Fibrometer (BioLiveScale, Angers, France) and Hepascore, which combine several variables like FibroTest, are under development.18, 19 All of these noninvasive tools have a rather good predictive positive value for diagnosis of nil or minimal fibrosis and extended fibrosis.17–20 Despite being a potential alternative to LB, routine use of these noninvasive tests is hampered by the cost of the device (Fibroscan), false negative or false positive results, or the need for standardization assays to perform the test (FibroTest).
The investigators of the AIDS Pegasys Ribavirin International Coinfection Trial (Apricot study),21 a pivotal trial evaluating the efficacy of pegylated interferon and ribavirin in patients coinfected with HIV and HCV, recently proposed a simple noninvasive test for liver fibrosis known as the FIB-4—a test derived from the Apricot database, which produces interesting results using the following formula: age (years) × AST [U/L]/(platelets [109/L] × (ALT [U/L])1/2).22 The FIB-4 index has an area under the receiver operating characteristic (ROC) curve of 0.76. A threshold value of <1.45 has a negative predictive value for the exclusion of extended fibrosis (F4-F6 in the Ishak classification) of 90%. A threshold value of >3.25 has a positive predictive value for the diagnosis of extended fibrosis of 65%.22
This study assessed the value of the FIB-4 index and its threshold values to differentiate mild to moderate fibrosis from advanced fibrosis in HCV-monoinfected patients and compared the FIB-4 index with FibroTest, the most widespread noninvasive score to assess fibrosis.
Patients and Methods
Comparison Between FIB-4 Index and LB Results.
We reviewed our computerized files of HCV-infected patients attending our unit and selected all the cases corresponding to the following criteria: (1) anti HCV- and HCV-RNA–positive; (2) LB prior to any antiviral therapy; (3) laboratory assessments allowing FIB-4 calculation (AST, ALT, platelet count) performed on the same day as LB or on the preceding day; (4) absence of HIV and HBV infection; (5) absence of heavy alcohol consumption (<40 g pure alcohol per day); (6) absence of other liver comorbidity, including hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, autoimmune hepatitis, and nonalcoholic steatohepatitis; and (7) absence of immune suppression. We used the FIB-4 index for semiquantitative evaluation of fibrosis in 847 HCV-monoinfected patients and compared the results with those of LBs performed the same day as the FIB-4 evaluation.
Comparison of FIB-4 Index and FibroTest Results.
We then selected all the HCV-infected cases who had available FibroTest results and the following criteria: (1) laboratory assessment allowing FIB-4 calculation (AST, ALT, platelet count) performed on the same day as FibroTest; (2) absence of HIV and HBV infection; (3) absence of heavy alcohol consumption (<40 g pure alcohol per day); (4) absence of other liver comorbidity including hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, autoimmune hepatitis or nonalcoholic steatohepatitis; (5) absence of immune suppression. We compared the FIB-4 index and FibroTest results on the same day in 780 cases, corresponding to 592 HCV-monoinfected patients.
Serum AST and ALT activities were routinely measured in our hospital (Laboratoire de Biochimie, Hôpital Necker, Paris, France); usual upper normal values were 45 IU/l for men and 40 IU/l for women and 65 IU/l for men and 50 IU/l for women, respectively. Platelet counts were performed in the same hospital (Laboratoire d'hématologie, Hŏpital Necker, Paris, France); normal values ranged between 150,000 and 500,000/mm3.
All LBs were analyzed in the same laboratory and all interpretations were supervised by a senior expert (V. V.). The degree of activity and the extent of fibrosis were assessed using the METAVIR index, which employs the following 2-letter and 2-number coding system: A = histological activity (A0 = no activity, A1 = mild activity, A2 = moderate activity, A3 = severe activity) and F = fibrosis (F0 = no fibrosis, F1 = portal fibrosis without bridges, F2 = portal fibrosis with rare bridges, F3 = numerous bridges without cirrhosis, and F4 = cirrhosis).5 FibroTest was calculated using biochemical values (γ-glutamyltransferase, haptoglobin, α2-macroglobulin, bilirubin, and apolipoprotein A1).
The FIB-4 values were calculated automatically using the formula: age (years) × AST [U/l]/(platelets [109/l] × (ALT [U/l])1/2), in which the age of the patient was the age at the time of the LB for the first comparison and the age at the time of FibroTest for the second comparison. The FIB-4 index was considered in the first Sterling study to delineate patients with no or moderate fibrosis (F0-F1-F2-F3) when the score is <1.45 from those with extensive fibrosis or cirrhosis (F4-F5-F6) when the score is >3.25 (in the ISHAK classification of fibrosis). The study was approved by the local ethics committee.
Results are presented as the mean ± SD, counts, and percentages. The FIB-4 results were compared with the METAVIR scores and FibroTest values, with contingency tables, κ, and areas under the ROC curve. All calculations were made using SPSS (version 18.104.22.168) software (SPPS Inc., Chicago, IL). A P value of less than 0.05 was considered statistically significant.
Comparison of FIB-4 Index and LB Results.
Eight hundred forty-seven patients infected by HCV alone fulfilled the selection criteria. The sample comprised 461 men and 386 women with a mean (±SD) age of 44 (±12) years. Serum ALT activity ranged from 5 to 1,053 IU/L (mean ± SD, 89 ± 78) and that of AST from 7 to 457 IU/L (mean ± SD, 55 ± 45); platelet count ranged from 56 × 109/L to 526 × 109/L with a mean value (±SD) of 205 ± 62. Regarding the distribution of fibrosis scores, 8.6% (n = 73) of the sample showed no fibrosis (METAVIR F0), 555.5% (n = 470) showed moderate fibrosis (F1), 18.7% (n = 158) showed intermediate fibrosis (F2), 10% (n = 85) showed extensive fibrosis (F3), and 7.2% (n = 61) showed cirrhosis (F4). Altogether, our sample resembled the usual repartition of pathological diagnosis in HCV-infected patients when they first come to the hospital.
On the whole sample, FIB-4 values ranged from 0.13 to 12.62. As shown in Fig. 1, mean values increased as a function of the fibrosis score, from 0.99 ± 0.66 in METAVIR F0 cases to 4.5 ± 2.8 in F4; however, the differences were only statistically significant (P < 0.01) when groups with severe fibrosis (F3 or F4) were compared with groups with no fibrosis (F0), moderate fibrosis (F1) or intermediate fibrosis (F2). Indeed, due to the rather large overlapping of the results, the FIB-4 index could not significantly discriminate F0 from F1 or F2 groups, nor F1 from F2.
The FIB-4 index enabled the correct identification of patients with severe fibrosis (METAVIR F3-F4) with an area under the ROC curve of 0.85 (95% CI 0.82-0.89) (Fig. 2). A FIB-4 index lower than 1.45 had a negative predictive value of 94.7% to exclude any extensive fibrosis (F3-F4) with a sensitivity of 74.3 % and a specificity of 80.1 % (Table 1). A FIB-4 index higher than 3.25 had a positive predictive value to confirm the existence of significant fibrosis (F3-F4) of 82.1% with a specificity of 98.2% and a sensitivity of 37.6% (Table 1). The FIB-4 index efficiently identified cirrhosis with an area under the ROC curve of 0.91 (95% CI 0.86-0.95). Using these cutoffs, 93.3% of the 617 biopsies with FIB-4 values outside the 1.45-3.25 range (72.8 of total liver biopsies) were correctly classified.
|FIB4 Index||Liver Biopsy (METAVIR)||Total|
|<1.45||94.7% (n = 521)||5.3% (n = 29)||550|
|1.45-3.25||73.0% (n = 168)||27.0% (n = 62)||230|
|>3.25||17.9% (n = 12)||82.1% (n = 55)||67|
|Total||82.8% (n = 701)||17.2% (n = 146)||847|
Comparison of FIB-4 Index and FibroTest Results.
Seven hundred eighty FibroTest results corresponding to 592 patients were available. The sample comprised 272 men and 320 women with a mean (±SD) age of 43 (±10) years. The FIB-4 index was concordant (κ = 0.561; P < 0.01) with the FibroTest results.
Of the 454 cases with an FIB-4 score <1.45, 418 (92.1%) were in agreement with the FibroTest results (METAVIR F0-F1-F2) to exclude severe fibrosis (F3-F4) (Table 2). The post hoc review of the files of 36 patients with a FIB-4/FibroTest discordance showed that discordant cases were imputed to a FibroTest failure in 23 cases because of a low haptoglobin level (n = 7), Gilbert's disease (n = 7), data capture failure (n = 1), or unexplained causes (n = 8); in these cases, liver fibrosis was overestimated by the FibroTest results. Thirteen cases were interpreted as an FIB-4 failure because of the young age of the patients (n = 5) and/or of unexplained thrombocytosis (n = 11); in these cases, liver fibrosis was underestimated by the FIB-4 results.
|FIB4 Index||FibroTest (METAVIR)||Total|
|<1.45||92.1% (n = 409)||7.9% (n = 35)||444|
|1.45-3.25||62.2% (n = 178)||37.8% (n = 108)||286|
|>3.25||24.0% (n = 12)||76.0% (n = 38)||50|
|Total||76.8% (n = 599)||23.2% (n = 181)||780|
Fifty cases had an FIB-4 score >3.25; 38 (76%) of them were concordant with the FibroTest results (METAVIR F3-F4) and 12 (24%) had discordant results (F0-F1-F2) (Table 2). The post hoc review of the files of 12 patients with a FIB-4/FibroTest discordance showed that discordant cases were mainly imputed to an FIB-4 failure due to old age (n = 6) and/or unexplained thrombopenia (n = 6), which overestimated liver fibrosis. FIB-4 index scores between 1.45 and 3.25 (35.4% of total cases) were not correlated to the FibroTest results.
Noninvasive markers of fibrosis, either biochemical (FibroTest) or morphological (elastometry), may replace LB in most cases in the diagnosis of fibrosis.8–20 These noninvasive tools have a rather good positive predictive value for the diagnosis of moderate or significant fibrosis.8–20 They are also simple, inexpensive, and easily reproducible. None of the available biomarkers actually meets these criteria. The device for elastometry is costly (≈70,000 euros); FibroTest supposes a standardization of the biochemical assays to be relevant, and there is a risk (as in LB) of overestimation or underestimation of fibrosis.23
The FIB-4 index may be of value in several respects. First, it is easy to use; the calculations are simple, quick, and do not require standardization. Second, results are available immediately, during the patient's visit. Third, it is inexpensive; there is no need to invest in a costly apparatus, and there are no additional costs, because the constitutive FIB-4 parameters are included in the standard investigation of any liver disease (age, AST, ALT, platelet count)—a fact that may be of particular importance in emerging countries, making the FIB-4 index a better test than the most evaluated noninvasive markers on the market. In terms of concordance with the results of LB and positive predictive value, it produces results similar to those obtained with other noninvasive markers of fibrosis,9, 10, 17–20 because ¾ of patients were classified correctly—a figure that correlates well with the performance of FibroTest.
The value of the area under the ROC curve for severe fibrosis (≥F3) was equal to 0.85, whereas those produced by the APRI, FibroTest, and FibroScan techniques were 0.84, 0.90, and 0.90, respectively.9, 10, 17 In particular, the FIB-4 index enabled the correct identification of extreme types of fibrosis, because its performance seemed to be reliable when identifying very moderate fibrosis versus more severe forms of the disease. The FIB-4 index, like other noninvasive tests, may replace 70% of biopsies.
A persistent problem is that noninvasive markers of fibrosis are compared with LB results, which remains the gold standard for fibrosis evaluation. However, LB can also over- or underestimate the degree of fibrosis.1, 4–7 It has recently been suggested that discordances between LB and FibroTest results could be explained by the technical difficulties involved in the examination of LB samples, which makes it unreliable. Poynard et al.23 observed discordances in 29% of patients that were due to marker failure and LB failure in 2.4% and 18% of cases, respectively. They showed that LB diagnostic failures were seven times more common than diagnostic failures due to markers. Furthermore, to evaluate diffuse liver diseases in a reliable manner, a specimen sample measuring at least 15 mm is needed.24 Bedossa et al.7 showed recently that only 65% of biopsies relying on 15-mm samples led to correct diagnoses (using the METAVIR score), whereas 75% of biopsies relying on 25-mm samples were correct. Because there were no benefits to taking bigger samples, the investigators suggested that 25-mm samples are necessary to evaluate fibrosis accurately.
Comparisons between the FIB-4 index and FibroTest results were performed in the second part of this study and showed a concordance of 92.1% for an FIB-4 index <1.45 and 76% for an FIB-4 index >3.25. Discordances were analyzed by reviewing the files of the patients. For an FIB-4 index <1.45, low haptoglobin or Gilbert's disease were the main causes of FibroTest failure, whereas young age and normal platelet count explained the FIB-4 failures. For an FIB-4 index >3.25, old age and low platelet count explained the FIB-4 failures. The FIB-4 index is more readily available than FibroTest because, contrary to FibroTest, it does not require standardization of biochemical values to be used in a reliable manner.
The key for future studies is to determine which combination of markers is the most reliable for first-line evaluation of fibrosis in HCV-infected patients and in what cases LB remains necessary. Castera et al.17 reported that the combination of FibroScan and FibroTest performed better than FibroScan, FibroTest, or the APRI tests alone performed in the same population, with areas under the ROC curve of 0.88 for ≥F2 and 0.95 for ≥F3. Sebastiani et al.25 found that a combination of APRI and FibroTest was accurate for the first-line evaluation of HCV-infected patients and improved the diagnostic performance, thus avoiding between 50% and 70% of LBs. More recently, Bourlière et al.26 showed that the combination of the APRI test, FibroTest, and Forns score in HCV-monoinfected patients allowed 191 of 235 (81.3%) patients to be correctly classified, thus avoiding LB.
The FIB-4 index is a new noninvasive test for the assessment of liver fibrosis. A score of <1.45 and >3.25 enables the correct identification of patients who have moderate or significant fibrosis, respectively, and could avoid LB examination. The FIB-4 index proved to be concordant with FibroTest results. Because the FIB-4 index is readily available, inexpensive, and easily reproducible, it could rapidly replace expensive and/or invasive methods to assess liver fibrosis, especially in emerging countries, to detect patients who need antiviral treatment and to monitor liver fibrosis progression (or regression). Other studies are now required to validate this new score in combination with other noninvasive tests to enhance its diagnostic performance, especially for intermediate values.
- 4Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97: 2614–2618., , , , , , et al.Direct Link:
- 12Biochemical markers of liver fibrosis: a comparison with historical features in patients with chronic hepatitis C. Am J Gastroenterol 2002; 97: 2419–2425., , , , .Direct Link:
- 26Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies. J Viral Hepat 2006; 13: 659–70., , , , , , et al.