Page 8 - NON-INVASIVE TESTS FOR EVALUATION OF LIVER DISEASE SEVERITY AND PROGNOSIS
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JOURNAL OF HEPATOLOGY
Table 4. Diagnostic performance of serum biomarkers of fibrosis for significant fibrosis (F P2) and cirrhosis (F4) in patients with chronic liver disease.
Biomarkers Etiologies Year Patients F≥2 F4 Cut-offs AUROC Se Sp CC
(n) (%) (%) (%) (%) (%)
FibroTest® [21] HCV 2001 339 80 >0.48 0.87 75 85 46
Forns Index [22] HCV 2002 476 26 30-94 51-95 45
APRI [23] HCV 2003 270 50 <4.2 >6.9 0.81 41-91 47-95 44
57-89 75-93 72
2004 ≤0.5 >1.5 0.80 77 73 75
2004 35-65 85-96 n.a.
2005 17 <1.0 ≥2.0 0.89 42-85 48-98 40-49
2005 63 89 92
FibroSpectII® [24] HCV 696 52 >0.36 0.83 71 89 n.a.
MP3 [25] HCV 2005 194 45 40-98 53-99 52
FPI [26] HCV 2005 302 48 <0.3 >0.4 0.82 80 70 n.a.
Hepascore® [27] HCV 2006 211 57 51-90 54-90 52
2007 ≤0.2 ≥0.8 0.77 30-40 97-97 35
2007 38-74 81-98 68
2008 ≥0.5 0.82 47-88 45-92 48
2005 37-88 50-88 49
2005 16 >0.84 0.89 40-98 28-90 35
2005 15-88 72-100 42
Lok index [28] HCV 2006 1141 38 <0.2 ≥0.5 0.81 70 97 62
GUCI [29] HCV 2004 179 87 51 n.a.
ViraHep-C [30] HCV 2005 398 12 >0.1 0.85 n.a. n.a. n.a.
Fibroindex [31] HCV 2007 360 80 84 82
FIB-4 [32] HCV 2008 830 37 ≤0.22 >0.55 0.83 43-77 97-97 68
HALT-C model [33] HCV 512 50 n.a. n.a. n.a.
Hui Score [36] HBV 235 ≤1.25 ≥2.25 0.83
Zeng score [37] HBV 372 25
SHASTA [38] HIV-HCV 95 58 17* <1.45 >3.25 0.85
FIB-4 [39] HIV-HCV 832 27
ELF® [34] Mixed 1021/496** 38 <0.2 ≥0.5 0.81
40
≤0.15 >0.5 0.79
<3.0 >8.7 0.77
<0.3 >0.8 0.87
22* <1.45 >3.25 0.76
0.102 0.78
12 n.a. 0.89
Fibrometer® [35] Mixed 598/503** 56 n.a. 0.89
NFS [40] NAFLD 733
BARD score [41] NAFLD 669 27* <-1.455 >0.676 0.82
30* ≥2 0.81
HCV, chronic hepatitis C; HBV, chronic hepatitis B; NAFLD, non-alcoholic fatty liver disease; AUROC, area under ROC curve; Se, sensitivity; Sp, specificity; CC, correctly
classified: true positive and negative; n.a., not available.
⁄F3F4.
⁄⁄HCV patients.
studies; the mean AUROC values of APRI in diagnosis of signifi- Recommendations
cant fibrosis and cirrhosis were 0.77 and 0.83, respectively.
Another meta-analysis of APRI in 1798 HBV patients found mean • Serum biomarkers of fibrosis are well validated in
AUROC values of 0.79 and 0.75 for significant fibrosis and cirrho- patients with chronic viral hepatitis (with more evidence
sis, respectively [106]. In the largest comparative study to date for HCV than for HBV and HIV/HCV coinfection). They
(n = 510 patients monoinfected with hepatitis B or C matched are less well validated in NAFLD and not validated in
on fibrosis stage), overall diagnostic performances of blood tests other chronic liver diseases (A1)
(FibroTestÒ, FibroMeterÒ, and HepaScoreÒ) were similar between
hepatitis B and C with AUROC ranging from 0.75 to 0.84 for sig- • Their performances are better for detecting cirrhosis
nificant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to than significant fibrosis (A1)
0.87 for cirrhosis, respectively [107].
• Caution is needed in patients with HIV-HCV coinfection
In HIV-HCV coinfected patients, performance of non-patented because of the risk of false positive results related
tests (e.g., APRI, FIB-4, and the Forns index) for predicting fibrosis to HIV-induced thrombocytopenia, antiretroviral
seems less accurate than in HCV-monoinfected patients: they are treatment-induced hyperbilirubinemia or increased
accurate for the diagnosis of cirrhosis, but relatively inaccurate serum γ-glutamyl transferase levels (A2)
for the diagnosis of significant fibrosis [108–110]. As for patented
tests, such as FibroTestÒ, FibroMeterÒ, and HepaScoreÒ, they out- • FibroTest®, APRI and NAFLD fibrosis score are the
perform the non-patented tests in HIV-HCV coinfection, particu- most widely used and validated patented and non-
larly for significant fibrosis [111,112]. Importantly, one should be patented tests (A2)
aware of false positive results with APRI and FIB-4 (related to
HIV-induced thrombocytopenia) as well as with FibroTestÒ and Comparative performance of patented and non-patented serum
HepaScoreÒ (related to hyperbilirubinemia induced by the use biomarkers for staging liver fibrosis
of antiretroviral treatment such as atanazavir) or FibroTestÒ
When compared and validated externally in patients with hep-
and Forns Index (related to increase in c-glutamyl transferase atitis C [120–125], the different patented tests had similar levels
of performance in diagnosis of significant fibrosis. In the largest
induced by nevirapine) [111]. independent study (1370 patients with viral hepatitis; 913 HCV
In patients with NAFLD, the NAFLD fibrosis score [40] is
currently the most studied [85,113–118] and validated bio-
marker [119]. The NAFLD fibrosis score seems to perform
better in Caucasians than Asians, probably related to the
ethical difference in fat distribution and its influence on the
BMI [102].
Journal of Hepatology 2015 vol. xxx j xxx–xxx 7
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
Table 4. Diagnostic performance of serum biomarkers of fibrosis for significant fibrosis (F P2) and cirrhosis (F4) in patients with chronic liver disease.
Biomarkers Etiologies Year Patients F≥2 F4 Cut-offs AUROC Se Sp CC
(n) (%) (%) (%) (%) (%)
FibroTest® [21] HCV 2001 339 80 >0.48 0.87 75 85 46
Forns Index [22] HCV 2002 476 26 30-94 51-95 45
APRI [23] HCV 2003 270 50 <4.2 >6.9 0.81 41-91 47-95 44
57-89 75-93 72
2004 ≤0.5 >1.5 0.80 77 73 75
2004 35-65 85-96 n.a.
2005 17 <1.0 ≥2.0 0.89 42-85 48-98 40-49
2005 63 89 92
FibroSpectII® [24] HCV 696 52 >0.36 0.83 71 89 n.a.
MP3 [25] HCV 2005 194 45 40-98 53-99 52
FPI [26] HCV 2005 302 48 <0.3 >0.4 0.82 80 70 n.a.
Hepascore® [27] HCV 2006 211 57 51-90 54-90 52
2007 ≤0.2 ≥0.8 0.77 30-40 97-97 35
2007 38-74 81-98 68
2008 ≥0.5 0.82 47-88 45-92 48
2005 37-88 50-88 49
2005 16 >0.84 0.89 40-98 28-90 35
2005 15-88 72-100 42
Lok index [28] HCV 2006 1141 38 <0.2 ≥0.5 0.81 70 97 62
GUCI [29] HCV 2004 179 87 51 n.a.
ViraHep-C [30] HCV 2005 398 12 >0.1 0.85 n.a. n.a. n.a.
Fibroindex [31] HCV 2007 360 80 84 82
FIB-4 [32] HCV 2008 830 37 ≤0.22 >0.55 0.83 43-77 97-97 68
HALT-C model [33] HCV 512 50 n.a. n.a. n.a.
Hui Score [36] HBV 235 ≤1.25 ≥2.25 0.83
Zeng score [37] HBV 372 25
SHASTA [38] HIV-HCV 95 58 17* <1.45 >3.25 0.85
FIB-4 [39] HIV-HCV 832 27
ELF® [34] Mixed 1021/496** 38 <0.2 ≥0.5 0.81
40
≤0.15 >0.5 0.79
<3.0 >8.7 0.77
<0.3 >0.8 0.87
22* <1.45 >3.25 0.76
0.102 0.78
12 n.a. 0.89
Fibrometer® [35] Mixed 598/503** 56 n.a. 0.89
NFS [40] NAFLD 733
BARD score [41] NAFLD 669 27* <-1.455 >0.676 0.82
30* ≥2 0.81
HCV, chronic hepatitis C; HBV, chronic hepatitis B; NAFLD, non-alcoholic fatty liver disease; AUROC, area under ROC curve; Se, sensitivity; Sp, specificity; CC, correctly
classified: true positive and negative; n.a., not available.
⁄F3F4.
⁄⁄HCV patients.
studies; the mean AUROC values of APRI in diagnosis of signifi- Recommendations
cant fibrosis and cirrhosis were 0.77 and 0.83, respectively.
Another meta-analysis of APRI in 1798 HBV patients found mean • Serum biomarkers of fibrosis are well validated in
AUROC values of 0.79 and 0.75 for significant fibrosis and cirrho- patients with chronic viral hepatitis (with more evidence
sis, respectively [106]. In the largest comparative study to date for HCV than for HBV and HIV/HCV coinfection). They
(n = 510 patients monoinfected with hepatitis B or C matched are less well validated in NAFLD and not validated in
on fibrosis stage), overall diagnostic performances of blood tests other chronic liver diseases (A1)
(FibroTestÒ, FibroMeterÒ, and HepaScoreÒ) were similar between
hepatitis B and C with AUROC ranging from 0.75 to 0.84 for sig- • Their performances are better for detecting cirrhosis
nificant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to than significant fibrosis (A1)
0.87 for cirrhosis, respectively [107].
• Caution is needed in patients with HIV-HCV coinfection
In HIV-HCV coinfected patients, performance of non-patented because of the risk of false positive results related
tests (e.g., APRI, FIB-4, and the Forns index) for predicting fibrosis to HIV-induced thrombocytopenia, antiretroviral
seems less accurate than in HCV-monoinfected patients: they are treatment-induced hyperbilirubinemia or increased
accurate for the diagnosis of cirrhosis, but relatively inaccurate serum γ-glutamyl transferase levels (A2)
for the diagnosis of significant fibrosis [108–110]. As for patented
tests, such as FibroTestÒ, FibroMeterÒ, and HepaScoreÒ, they out- • FibroTest®, APRI and NAFLD fibrosis score are the
perform the non-patented tests in HIV-HCV coinfection, particu- most widely used and validated patented and non-
larly for significant fibrosis [111,112]. Importantly, one should be patented tests (A2)
aware of false positive results with APRI and FIB-4 (related to
HIV-induced thrombocytopenia) as well as with FibroTestÒ and Comparative performance of patented and non-patented serum
HepaScoreÒ (related to hyperbilirubinemia induced by the use biomarkers for staging liver fibrosis
of antiretroviral treatment such as atanazavir) or FibroTestÒ
When compared and validated externally in patients with hep-
and Forns Index (related to increase in c-glutamyl transferase atitis C [120–125], the different patented tests had similar levels
of performance in diagnosis of significant fibrosis. In the largest
induced by nevirapine) [111]. independent study (1370 patients with viral hepatitis; 913 HCV
In patients with NAFLD, the NAFLD fibrosis score [40] is
currently the most studied [85,113–118] and validated bio-
marker [119]. The NAFLD fibrosis score seems to perform
better in Caucasians than Asians, probably related to the
ethical difference in fat distribution and its influence on the
BMI [102].
Journal of Hepatology 2015 vol. xxx j xxx–xxx 7
Please cite this article in press as: EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J
Hepatol (2015), http://dx.doi.org/10.1016/j.jhep.2015.04.006
