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