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JOURNAL OF HEPATOLOGY
Table 2. Currently available serum biomarkers for non-invasive evaluation of liver fibrosis in chronic liver disease.
HCV
Fibrotest® (Biopredictive, Paris, France) patented formula combining α-2-macroglobulin, γGT, apolipoprotein A1, haptoglobin, total
bilirubin, age and gender
Forns Index = 7.811 - 3.131 x ln(platelet count) + 0.781 x ln(GGT) + 3.467 x ln(age) - 0.014 x (cholesterol)
AST to Platelet Ratio (APRI) = AST (/ULN)/platelet (109/L) x 100
FibroSpectII® (Promotheus Laboratory Inc, San Diego, USA) patented formula combining α-2-macroglobulin, hyaluronate and TIMP-1
MP3 = 0.5903 x log(PIIINP [ng/ml]) - 0.1749 x log(MMP-1 [ng/ml])
Enhanced Liver Fibrosis score® (ELF) (Siemens Healthcare, Erlangen, Germany) patented formula combining age, hyaluronate,
MMP-3 and TIMP-1
Fibrosis Probability Index (FPI) = 10.929 + (1.827 x Ln[AST]) + (0.081 x age) + (0.768 x past alcohol use*) + (0.385 x HOMA-IR) -
(0.447 x cholesterol)
Hepascore® (PathWest, University of Western Australia, Australia) patented formula combining bilirubin, γGT, hyaluronate, α-2-
macroglobulin, age and gender
Fibrometer® (Echosens, Paris, France) patented formula combining platelet count, prothrombin index, AST, α-2-macroglobulin,
hyaluronate, urea and age
Lok index = -5.56 - 0.0089 x platelet (103/mm3) + 1.26 x AST/ALT ratio = 5.27 x INR
Gotebörg University Cirrhosis Index (GUCI) = AST x prothrombin - INR x 100/platelet
Virahep-C model = -5.17 + 0.20 x race + 0.07 x age (yr) + 1.19 ln(AST [IU/L]) - 1.76 ln(platelet count [103/ml]) + 1.38 ln(alkaline phos-
phatase [IU/L])
Fibroindex = 1.738 - 0.064 x (platelets [104/mm3]) + 0.005 x (AST [IU/L]) + 0.463 x (gamma globulin [g/dl])
HALT-C model = -3.66 - 0.00995 x platelets (103/ml) + 0.008 x serum TIMP-1 + 1.42 x log(hyaluronate)
HBV
Hui score = 3.148 + 0.167 x BMI + 0.088 x bilirubin - 0.151 x albumin - 0.019 x platelet
Zeng score = -13.995 + 3.220 log(α-2-macroglobulin) + 3.096 log(age) + 2.254 log(GGT) + 2.437 log(hyaluronate)
HIV-HCV
FIB-4 = age (yr) x AST [U/L]/(platelets [109/L] x (ALT [U/L])1/2
SHASTA index = -3.84 + 1.70 (1 if HA 41-85 ng/ml, 0 otherwise) + 3.28 (1 if HA >85 ng/ml, 0 otherwise) + 1.58 (albumin <3.5 g/dl,
0 otherwise) + 1.78 (1 if AST >60 IU/L, 0 otherwise)
NAFLD
NAFLD Fibrosis Score (NFS) = (-1.675 + 0.037 x age (yr) + 0.094 x BMI (kg/m2) + 1.13 x IFG/diabetes (yes = 1, no = 0) + 0.99 x AST/
ALT ratio - 0.013 x platelet count (x109/L) - 0.66 x albumin [g/dl])
BARD score (BMI ≥28 = 1; AST/ALT ratio ≥0.8 = 2; diabetes = 1; score ≥2, odds ratio for advanced fibrosis = 17)
⁄Graded as 0–2.
summarized in Table 2. The FibroTestÒ (proprietary formula; instance, increased levels of hyaluronate occur in the post-pran-
Biopredictive, Paris, France, licensed under the name of dial state [45] or in aged patients with chronic inflammatory pro-
FibrosureÒ in the USA (LabCorp, Burlington, NC, USA)) was the cesses such as rheumatoid arthritis [46]. Also, the reproducibility
first algorithm combining several parameters [21]. Several other of measurement of some parameters included in ‘‘indirect’’ serum
scores or algorithms have been proposed in hepatitis C virus markers, such as aspartate aminotransferase (AST) levels or pla-
(HCV) [22–35], as well as in hepatitis B virus (HBV) [36,37], telet count, is questionable [47]. In addition, the interpretation
human immunodeficiency virus (HIV)-HCV coinfection [38,39], of each test requires a critical analysis in order to avoid false posi-
and NAFLD [40,41]. Four are protected by patents and tive or false negative results. For instance, when using FibroTestÒ,
commercially available: the FibroMeterÒ (Echosens, Paris, the existence of hemolysis or Gilbert syndrome that can lead to
France), the FibroSpectIIÒ (Prometheus Laboratory Inc. San false positive results (by a decrease haptoglobin or an increase
Diego, CA, USA), the ELFÒ (Enhanced Liver Fibrosis Test, in bilirubin, respectively) should be taken into account [48].
Siemens Healthcare, Erlangen, Germany) and the HepaScoreÒ Similarly, acute hepatitis can produce false positive results in
(PathWest, University of Western Australia, Australia). Non- the aspartate-to-platelet ratio index (APRI), Forns index, FIB-4
patented methods use published models, based on routinely or FibroMeterÒ tests, since all include serum levels of amino-
available laboratory values. transferases in their formulas.
The practical advantages of analyzing serum biomarkers to Liver stiffness measurement
measure fibrosis include their high applicability (>95%) [42], their
good inter-laboratory reproducibility [43,44], and their potential Transient elastography
widespread availability (non-patented) (Table 3). However, none Liver fibrosis can be staged using 1-dimensional ultrasound TE
are liver specific and their results may be influenced by changes (FibroScan(R), Echosens, Paris, France) [49], which measures the
in clearance and excretion of each individual parameters. For
Journal of Hepatology 2015 vol. xxx j xxx–xxx 3
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 2. Currently available serum biomarkers for non-invasive evaluation of liver fibrosis in chronic liver disease.
HCV
Fibrotest® (Biopredictive, Paris, France) patented formula combining α-2-macroglobulin, γGT, apolipoprotein A1, haptoglobin, total
bilirubin, age and gender
Forns Index = 7.811 - 3.131 x ln(platelet count) + 0.781 x ln(GGT) + 3.467 x ln(age) - 0.014 x (cholesterol)
AST to Platelet Ratio (APRI) = AST (/ULN)/platelet (109/L) x 100
FibroSpectII® (Promotheus Laboratory Inc, San Diego, USA) patented formula combining α-2-macroglobulin, hyaluronate and TIMP-1
MP3 = 0.5903 x log(PIIINP [ng/ml]) - 0.1749 x log(MMP-1 [ng/ml])
Enhanced Liver Fibrosis score® (ELF) (Siemens Healthcare, Erlangen, Germany) patented formula combining age, hyaluronate,
MMP-3 and TIMP-1
Fibrosis Probability Index (FPI) = 10.929 + (1.827 x Ln[AST]) + (0.081 x age) + (0.768 x past alcohol use*) + (0.385 x HOMA-IR) -
(0.447 x cholesterol)
Hepascore® (PathWest, University of Western Australia, Australia) patented formula combining bilirubin, γGT, hyaluronate, α-2-
macroglobulin, age and gender
Fibrometer® (Echosens, Paris, France) patented formula combining platelet count, prothrombin index, AST, α-2-macroglobulin,
hyaluronate, urea and age
Lok index = -5.56 - 0.0089 x platelet (103/mm3) + 1.26 x AST/ALT ratio = 5.27 x INR
Gotebörg University Cirrhosis Index (GUCI) = AST x prothrombin - INR x 100/platelet
Virahep-C model = -5.17 + 0.20 x race + 0.07 x age (yr) + 1.19 ln(AST [IU/L]) - 1.76 ln(platelet count [103/ml]) + 1.38 ln(alkaline phos-
phatase [IU/L])
Fibroindex = 1.738 - 0.064 x (platelets [104/mm3]) + 0.005 x (AST [IU/L]) + 0.463 x (gamma globulin [g/dl])
HALT-C model = -3.66 - 0.00995 x platelets (103/ml) + 0.008 x serum TIMP-1 + 1.42 x log(hyaluronate)
HBV
Hui score = 3.148 + 0.167 x BMI + 0.088 x bilirubin - 0.151 x albumin - 0.019 x platelet
Zeng score = -13.995 + 3.220 log(α-2-macroglobulin) + 3.096 log(age) + 2.254 log(GGT) + 2.437 log(hyaluronate)
HIV-HCV
FIB-4 = age (yr) x AST [U/L]/(platelets [109/L] x (ALT [U/L])1/2
SHASTA index = -3.84 + 1.70 (1 if HA 41-85 ng/ml, 0 otherwise) + 3.28 (1 if HA >85 ng/ml, 0 otherwise) + 1.58 (albumin <3.5 g/dl,
0 otherwise) + 1.78 (1 if AST >60 IU/L, 0 otherwise)
NAFLD
NAFLD Fibrosis Score (NFS) = (-1.675 + 0.037 x age (yr) + 0.094 x BMI (kg/m2) + 1.13 x IFG/diabetes (yes = 1, no = 0) + 0.99 x AST/
ALT ratio - 0.013 x platelet count (x109/L) - 0.66 x albumin [g/dl])
BARD score (BMI ≥28 = 1; AST/ALT ratio ≥0.8 = 2; diabetes = 1; score ≥2, odds ratio for advanced fibrosis = 17)
⁄Graded as 0–2.
summarized in Table 2. The FibroTestÒ (proprietary formula; instance, increased levels of hyaluronate occur in the post-pran-
Biopredictive, Paris, France, licensed under the name of dial state [45] or in aged patients with chronic inflammatory pro-
FibrosureÒ in the USA (LabCorp, Burlington, NC, USA)) was the cesses such as rheumatoid arthritis [46]. Also, the reproducibility
first algorithm combining several parameters [21]. Several other of measurement of some parameters included in ‘‘indirect’’ serum
scores or algorithms have been proposed in hepatitis C virus markers, such as aspartate aminotransferase (AST) levels or pla-
(HCV) [22–35], as well as in hepatitis B virus (HBV) [36,37], telet count, is questionable [47]. In addition, the interpretation
human immunodeficiency virus (HIV)-HCV coinfection [38,39], of each test requires a critical analysis in order to avoid false posi-
and NAFLD [40,41]. Four are protected by patents and tive or false negative results. For instance, when using FibroTestÒ,
commercially available: the FibroMeterÒ (Echosens, Paris, the existence of hemolysis or Gilbert syndrome that can lead to
France), the FibroSpectIIÒ (Prometheus Laboratory Inc. San false positive results (by a decrease haptoglobin or an increase
Diego, CA, USA), the ELFÒ (Enhanced Liver Fibrosis Test, in bilirubin, respectively) should be taken into account [48].
Siemens Healthcare, Erlangen, Germany) and the HepaScoreÒ Similarly, acute hepatitis can produce false positive results in
(PathWest, University of Western Australia, Australia). Non- the aspartate-to-platelet ratio index (APRI), Forns index, FIB-4
patented methods use published models, based on routinely or FibroMeterÒ tests, since all include serum levels of amino-
available laboratory values. transferases in their formulas.
The practical advantages of analyzing serum biomarkers to Liver stiffness measurement
measure fibrosis include their high applicability (>95%) [42], their
good inter-laboratory reproducibility [43,44], and their potential Transient elastography
widespread availability (non-patented) (Table 3). However, none Liver fibrosis can be staged using 1-dimensional ultrasound TE
are liver specific and their results may be influenced by changes (FibroScan(R), Echosens, Paris, France) [49], which measures the
in clearance and excretion of each individual parameters. For
Journal of Hepatology 2015 vol. xxx j xxx–xxx 3
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
