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NON INVASIVE ASSESSMENT OF NON INVASIVE ASSESSMENT OF LIVER FIBROSIS : FIBROSCAN LIVER FIBROSIS : FIBROSCAN
M. BeaugrandM. BeaugrandService dService d’’HHéépatologiepatologie
Hopital J. VerdierHopital J. VerdierBONDY 93143BONDY 93143
et Universitet Universitéé Paris XIIIParis XIII
MAINZ 21.09.2008
ASSESSMENT OF FIBROSIS : WHY ?ASSESSMENT OF FIBROSIS : WHY ?
Management Management ofof individualindividual patientspatients•• SignificantSignificant fibrosisfibrosis TreatmentTreatment•• CirrhosisCirrhosis ScreeningScreening for varices for varices andand HCCHCC
ScreeningScreening for for cirrhosiscirrhosis or extensive or extensive fibrosisfibrosis•• In In highhigh riskrisk patientspatients•• In In thethe generalgeneral populationpopulation
Evaluation Evaluation ofof treatmentstreatments•• Antiviral Antiviral andand antifibroticantifibrotic drugsdrugs
2.5 cm
4 cm1 cm ∅
Volume
ELASTOMETRY (FIBROSCAN)ELASTOMETRY (FIBROSCAN)
Probe
Sandrin et al. Ultrasound Med Biol 2003;29:1-8
LB x 100
HOW TO MEASURE ELASTICITY ?HOW TO MEASURE ELASTICITY ?
GenerateGenerate an an elasticelasticShearShear vawevawe
MeasureMeasure itsits speadspead VsVs
ElasticityElasticityE E ∝ VVSS
22
2.5 cm
4 cm
1 cm ∅
Volume of exploration
Volume of exploration > 3 cmVolume of exploration > 3 cm33
Probe position
Probe
INTER OBSERVER INTER OBSERVER REPRODUCTIBILITY OF LSMREPRODUCTIBILITY OF LSM
Fraquelli et al, Gut 2007
PATIENTS WITH HCV CHRONIC HEPATITISPATIENTS WITH HCV CHRONIC HEPATITIS
327 HCV + patientswith no ascites
251 patients included
53 patients excludedbiopsy not suitable for fibrosis stage assessment: less than 10 portal tracts in the absence of
cirrhosis
23 patients excluded:unreliable stiffness measurement: success rate less than 60% upon
10 measurements
Small biopsy126 patients
Large biopsy125 patients
BOX PLOTS. N=251BOX PLOTS. N=251
F01 F2 F3 F410
0
101
102
Ela
stic
ity (k
Pa)
Fibrosis stage0-1 2 3 4
100
1
10
Fibrosis stage (METAVIR)
median IQR
maximum
minimum
Legend
Sti
ffn
ess
(kP
a)
(lo
gari
thm
ic s
cale
)
0.0
0.2
0.4
0.6
0.8
1.0
0.0 0.2 0.4 0.6 0.8 1.01-Specificité
Sens
ibili
té
F01 / F234
F012 / F34
F0123 / F4
AUROCAUROC( CONFIDENCE ( CONFIDENCE INTERVALS 95%)INTERVALS 95%)
-- FF≥≥2 : 0.79 (0.732 : 0.79 (0.73--0.84)0.84)-- FF≥≥3 : 0.91 (0.873 : 0.91 (0.87--0.96)0.96)-- F=4 : 0.97 (0.93F=4 : 0.97 (0.93--1.00)1.00)
F≥2
F≥3
F=4
ROC CURVESROC CURVES
UNI AND MULTIVARIATE ANALYSISUNI AND MULTIVARIATE ANALYSIS
UnivariateUnivariate analysisanalysis (Kendall(Kendall’’s coefficient)s coefficient)
FibrosisFibrosis ActivityActivity SteatosisSteatosisStiffnessStiffness rr 0.550.55 0.210.21 0.190.19
pp <0.0001<0.0001 0.00030.0003 0.00080.0008
FibrosisFibrosis rr -- 0.360.36 0.170.17pp -- <0.0001<0.0001 0.0080.008
Multivariate analysisMultivariate analysis (multiple regression)(multiple regression)
Only fibrosisOnly fibrosis was significantly correlated to liver stiffness was significantly correlated to liver stiffness measurement.measurement.
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1
1 - Specificity
Sens
itivi
ty
F01 versus F234
F012 versus F34
F0123 versus F4
VALIDATION OF DIAGNOSIS ACCURACY IN AN INDEPENDENT HCV POPULATION
Total number of included patients: 639Number of unreliable liver samples: 86 (13%)Number of unreliable LSM: 59 (9%)Patients kept for statistical analysis : 494
1010151527274477%%
3131--100100
1111--3030
11--101000SS
SteatosisSteatosis
333535565666%%33221100AA
114410103131393966%%
4433221100FF
METAVIRMETAVIR
Univariate Spearman correlationMETAVIR F: 0.70 (p << 0.001)METAVIR A: 0.45 (p << 0.001)Steatosis: 0.35 (p << 0.001)
Area under ROC curves(95% confidence interval)F01 versus F234 = 0.84 (0.80-0.87)F012 versus F34 = 0.93 (0.90-0.95)F0123 versus F4 = 0.96 (0.94-0.98)
-- ResultsResults
-- 103 Patients103 PatientsCauses : Causes : 71 VHC71 VHC
14 VHB14 VHB15 VHC+HIV15 VHC+HIV2 VHB+HIV2 VHB+HIV1 VHC+VHB1 VHC+VHB
≥ F2 ≥ F3 = F4
AUROC 0.94 0.95 0.93
LIVER BIOPSIES > 30 mmLIVER BIOPSIES > 30 mm
F0 F1 F2 F3 F4N 9 58 14 7 15
Fibrosis Score :
CUTCUT--OFF VALUESOFF VALUES**
ThresholdThreshold SensitivitySensitivity SpecificitySpecificity LRLR(kPa)(kPa)
FF ≥≥ 22 8.78.7 0.550.55 0.840.84 3.53.5FF ≥≥ 33 9.69.6 0.840.84 0.850.85 5.75.7F F = 4= 4 14.514.5 0.840.84 0.940.94 13.013.0
* Obtained by the jack* Obtained by the jack--knife method.knife method.
The optimum thresholds were chosen to maximize the The optimum thresholds were chosen to maximize the sum of sensitivity and specificity.sum of sensitivity and specificity.
FIBROSCAN IN HBV PATIENTS202 patients
- 15 non interpretable biopsies
- 14 LSM considered as non reliable
Statistical analysis on 173 patients
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 1
1 - Specificity
Sens
itivi
ty
F01 versus F234
F0123 versus F34
F0123 versus F4
AUROC
F01 versus F234: 0.81 (0.73-0.86)
F012 versus F34: 0.93 (0.88-0.96)
F0.123 versus F4: 0.93 (0.82-0.98)
FIBROSCAN VERSUS BLOOD TESTSFIBROSCAN VERSUS BLOOD TESTS
1
10
100
F1 F2 F3 F4
Fibrosis stage
1
10
100
F1 F2 F3 F4
Fibrosis stage
0.0
0.3
0.7
1.0
F1 F2 F3 F4
Fibrosis stage
0.0
2.0
4.0
6.0
F1 F2 F3 F4
Fibrosis stage
Elas
ticité
(kPa
)
FibroScan FibroTest APRI
Score METAVIR de fibrose Score METAVIR de fibrose Score METAVIR de fibrose
Castera Al. Gastroenterology 2005
CONCORDANCE WITH LIVER BIOPSYCONCORDANCE WITH LIVER BIOPSY
F01/F234 F012/F34 F0123/F4APRI 0.78 0.84 0.83FibroTest 0.85 0.90 0.87FibroScan 0.83 0.90 0.95Combinaison 0.88 0.95 0.95FibroTest+FibroScan
• AUROC
• Percentage of concording results
F01/F234 F0123/F4FibroTest 80 81FibroScan 73 83Combinaison 84 95FibroTest+FibroScan
FIBROSCAN / BLOOD TESTSFIBROSCAN / BLOOD TESTS
PhysicalPhysical parameterparameter ManyMany biologicalbiological parametersparametersdirectlydirectly linkedlinked fofo fibrosisfibrosis notnot directlydirectly relatedrelated to to fibrosisfibrosis
andand proneprone to to thethe influence influence ofofextra extra hepatichepatic conditionsconditions
OneOne single single devicedevice DozensDozens ofof predictivepredictive teststests
FIBROSISFIBROSIS
≠≠
FIBROSIS STAGEFIBROSIS STAGE
Acute HDV hepatitis Sarcoïdosis
Alcoholic cirrhosis Normal liver
2040
6080
2040
6080
50 50
Chronic hepatitis rho=0.50; p<0.0001 Cirrhosis rho=0.43; p=0.005
Steatohepatitis rho=0.22; p=0.16 All patients rho=0.60; p<0.0001
Live
rstif
fnes
s(k
Pa)
Fibrosis fraction area (%)
2040
6080
2040
6080
50 50
Chronic hepatitis rho=0.50; p<0.0001 Cirrhosis rho=0.43; p=0.005
Steatohepatitis rho=0.22; p=0.16 All patients rho=0.60; p<0.0001
Live
rstif
fnes
s(k
Pa)
Fibrosis fraction area (%)
Figure 2
SCREENING IN HIGH RISK PATIENTSSCREENING IN HIGH RISK PATIENTS
41
34
33
LSM
Blood tests
Confirmation of cirrhosis
LB
LSM>13 kPayes
Absence ofcirrhosis
Suspectedcirrhosis
no
227 patients in alcoholicabstinence program
CONCLUSIONCONCLUSION
1)1) In patients In patients withwith chronicchronic live live diseasedisease LSM LSM reflectsreflects thethe arrountarrount ofof liverliver fibrosisfibrosis..
2)2) ItIt hashas particularlyparticularly goodgood performances for performances for thethediagnosisdiagnosis ofof cirrhosiscirrhosis
3)3) Fibroscan Fibroscan mightmight bebe a a reliablereliable screeningscreening tooltoolfor for thethe diagnosisdiagnosis ofof cirrhosiscirrhosis in in highhigh riskriskgroups or groups or eveneven in in thethe generalgeneral population.population.
FUTUREFUTURE
ImprovementsImprovements to to comecome•• ImprovementImprovement in softwarein software•• New probes for New probes for obeseobese patients patients andand alsoalso for for
childrenchildren (or patients (or patients withwith smallsmall intercostal intercostal spacesspaces
Future Future developmentsdevelopments•• 1 D 1 D measurementsmeasurements•• 2 D 2 D imagingimaging
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