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Michel BEAUGRANDMichel BEAUGRAND
EVALUATION OF LIVER FIBROSISEVALUATION OF LIVER FIBROSISBLOOD TESTS, LIVER BIOPSY AND BLOOD TESTS, LIVER BIOPSY AND
FIBROSCANFIBROSCAN
M. BeaugrandM. Beaugrand
Service d’HépatologieService d’Hépatologie
Hopital J. VerdierHopital J. Verdier
BONDY 93143BONDY 93143
et Université Paris XIIIet Université Paris XIII
PHC JANUARY 07
EVALUATION OF FIBROSIS : WHY ?EVALUATION OF FIBROSIS : WHY ?
Causal agentCausal agent
Chronic liver Chronic liver
DiseaseDisease
CirrhosisCirrhosis
DecompensationDecompensation Hepatocellular Hepatocellular
2 % to 5 % per year2 % to 5 % per year carcinoma carcinoma
2 % to 5 % per year2 % to 5 % per year
Death
4 % per year
Fibrosis
Distorted architecture
Portal hypertension
Liver failure
Carcinogenesis
FIBROSIS
ASSESSMENT OF FIBROSIS : WHY ?ASSESSMENT OF FIBROSIS : WHY ?
Management of individual patientsManagement of individual patients• Significant fibrosisSignificant fibrosis TreatmentTreatment• CirrhosisCirrhosis Screening for varices and HCCScreening for varices and HCC
Evaluation of treatmentsEvaluation of treatments• Antiviral and antifibrotic drugsAntiviral and antifibrotic drugs
Screening for cirrhosis or extensive fibrosisScreening for cirrhosis or extensive fibrosis• In high risk patientsIn high risk patients
EVALUATION OF FIBROSIS : HOW ?EVALUATION OF FIBROSIS : HOW ?
- Liver biopsy- Liver biopsy
- Blood tests- Blood tests• Genuine serum markers of fibrosis : Genuine serum markers of fibrosis :
by products of extracellular matrixby products of extracellular matrix
metabolism.metabolism.
• Probabilistic indexes = surrogate markers.Probabilistic indexes = surrogate markers.
- Fibroscan - Fibroscan ( transcient elastography)( transcient elastography)
LIVER BIOPSY : LIMITATIONSLIVER BIOPSY : LIMITATIONS
• AcceptabilityAcceptability- patients are often reluctant- patients are often reluctant- even some doctors are reluctant- even some doctors are reluctant
• CostCost• MorbidityMorbidity• ReliabilityReliability
- liver sample size ideally - liver sample size ideally ≥ 25 mm≥ 25 mm- pathologist’s experience- pathologist’s experience- suboptimal reproductibility of scoring systems- suboptimal reproductibility of scoring systems- quantitative assessment unpractical- quantitative assessment unpractical
LENGH OF LIVER BIOPSYLENGH OF LIVER BIOPSY
Biopsy length
Bedossa et al, Hepatology 2003
LIVER BIOPSY : PROS AND CONSLIVER BIOPSY : PROS AND CONS
PROPRO. Not influenced by extrahepatic conditions . Not influenced by extrahepatic conditions . Allows analysis of elementary lesions and comobidities. Allows analysis of elementary lesions and comobidities. May allow assessment of fibrogenesis (molecular . May allow assessment of fibrogenesis (molecular biology)biology)
CONCON. Sampling error. Sampling error. Dependant of pathologist’s experience. Dependant of pathologist’s experience. Unavalaible in large parts of the world. Unavalaible in large parts of the world
BLOOD TESTSBLOOD TESTS
Matrix relatedMatrix relatedPIIINP, collagen type IV, lamininPIIINP, collagen type IV, lamininHyaluronic acid, MMP, TIMPHyaluronic acid, MMP, TIMP
Non maxtrix relatedNon maxtrix relatedAST, ALT, gamma GTAST, ALT, gamma GTBilirubin, prothrombine, plateletsBilirubin, prothrombine, plateletsGammaglobulins, ferritinGammaglobulins, ferritinAlpha 2 macroglobulin, haptoglobinAlpha 2 macroglobulin, haptoglobinApo A1, cholesterol, HOMAApo A1, cholesterol, HOMA
Poynard, 1991Poynard, 1991 Prothrombine, GGT, Apo A1Prothrombine, GGT, Apo A1 PGAPGA
Bonacini, 1997Bonacini, 1997 AST/ALAT, platelets, prothrombineAST/ALAT, platelets, prothrombineImbert-Bismut,Imbert-Bismut, 20012001 bili, GGT, hapto., a2MG, apoA1bili, GGT, hapto., a2MG, apoA1 FibrotestFibrotestLuo,Luo, 20022002 glob/alb, platelets, AST/ALTglob/alb, platelets, AST/ALTForns,Forns, 20022002 age, GGT, cholesterol, plateletsage, GGT, cholesterol, plateletsKaul,Kaul, 20022002 sex, ang.spider angiomas, AST, plateletssex, ang.spider angiomas, AST, plateletsWai, 2003Wai, 2003 AST/plateletsAST/platelets APRIAPRISud, 2004Sud, 2004 age, AST, cholesterol, HOMA, alcoholage, AST, cholesterol, HOMA, alcoholLainé, 2004Lainé, 2004 hyaluronate, transferinhyaluronate, transferinRosenberg,Rosenberg, 20042004 age, hyalur., col IV, col VI, laminin, PIIINP, TIMP-1 age, hyalur., col IV, col VI, laminin, PIIINP, TIMP-1 ELFELFPatel,Patel, 20042004 TIMP-1, a2MG, hyaluronateTIMP-1, a2MG, hyaluronate FibrospectFibrospectLeroy,Leroy, 20042004 PIIIMP, MMP1PIIIMP, MMP1Hui,Hui, 20052005 BMI, platelets, albumin, bilirubinBMI, platelets, albumin, bilirubinLok,Lok, 20052005 AST/ALT, platelets, INRAST/ALT, platelets, INRAdams,Adams, 20052005 bili, GGT, hyaluronate, a2MG, age, sexbili, GGT, hyaluronate, a2MG, age, sex HepascoreHepascoreCales,Cales, 20052005 AST, platelets, prothrombine, hyaluronate, AST, platelets, prothrombine, hyaluronate, FibrometreFibrometre
urea, ageurea, age
BLOOD TESTSBLOOD TESTS
Imbert-Bismut et al. Lancet 2001;357:2069-75Imbert-Bismut et al. Lancet 2001;357:2069-75
Fibrotest ®Fibrotest ®
BLOOD TESTSBLOOD TESTS
MetavirMetavirindexindex
VHC (n= 339)VHC (n= 339)
Imbert-Bismut et al. Lancet 2001;357:2069-75Imbert-Bismut et al. Lancet 2001;357:2069-75
Fibrotest ®Fibrotest ®
BLOOD TESTSBLOOD TESTS
HCV (n=339)
Métavir ≥ F2
AUC = 0,827
Index < 0,10 NPV 100% Index > 0,60 PPV > 90%
Liver Biopsy: - 46%
BLOOD TESTSBLOOD TESTS
Ref.Ref. TestTest AUCAUC
ConstructionConstruction ValidationValidation
Imbert-Bismut, 2001Imbert-Bismut, 2001 FibrotestFibrotest 0.830.83 0.850.85
Forns, 2002Forns, 2002 0.860.86 0.810.81
Wai, 2003Wai, 2003 APRIAPRI 0.800.80 0.880.88
Patel, 2004Patel, 2004 FibrospectFibrospect 0.830.83
Rosenberg, 2004Rosenberg, 2004 ELFELF 0.780.78
Leroy, 2004Leroy, 2004 0.820.82
Sud, 2004Sud, 2004 0.840.84
Adams, 2005Adams, 2005 HepascoreHepascore 0.850.85 0.820.82
HCV : F0-1 vs F2-3-4F0-1 vs F2-3-4HCV : F0-1 vs F2-3-4F0-1 vs F2-3-4
BLOOD TESTSBLOOD TESTS
Ref.Ref. TestTest AUCAUC
ConstructionConstruction ValidationValidation
Kaul, 2002Kaul, 2002 0.940.94
Wai, 2003Wai, 2003 APRIAPRI 0.890.89 0.940.94
Rosenberg, 2004Rosenberg, 2004 ELFELF 0.890.89
Le Calvez, 2004Le Calvez, 2004 FibrotestFibrotest 0.920.92
Adams, 2005Adams, 2005 HepascoreHepascore 0.940.94 0.890.89
Lok, 2005Lok, 2005 0.780.78 0.810.81
HCV : F0-1-2-3 vs F4 (cirrhosis)F0-1-2-3 vs F4 (cirrhosis)HCV : F0-1-2-3 vs F4 (cirrhosis)F0-1-2-3 vs F4 (cirrhosis)
PROPRO
. Easy, non invasive,not too costy. Easy, non invasive,not too costy
. Allow to split patients in 3 groups. Allow to split patients in 3 groups- those without significant fibrosis- those without significant fibrosis- those with extensive fibrosis or cirrhosis- those with extensive fibrosis or cirrhosis- intermediate- intermediate
CONCON
. Studied mainly in naive patients with HCV chronic hepatitis. Studied mainly in naive patients with HCV chronic hepatitis
. External validation lacking (except fibrotest). External validation lacking (except fibrotest)
. Require standardisation of biochemical methods. Require standardisation of biochemical methods
. Poorer performances in HBV patients or coinfected HCV-HIV. Poorer performances in HBV patients or coinfected HCV-HIV
. Possible influence of extrahepatic conditions. Possible influence of extrahepatic conditions
. No international consensus. No international consensus
BLOOD TESTS : PROS AND CONSBLOOD TESTS : PROS AND CONS
2.5 cm
4 cm
1 cm
Volume
ELASTOMETRY (FIBROSCAN)ELASTOMETRY (FIBROSCAN)
ProbeProbe
Sandrin et al. Ultrasound Med Biol 2003;29:1-8Sandrin et al. Ultrasound Med Biol 2003;29:1-8
LB x 100LB x 100
HOW TO MEASURE ELASTICITY ?HOW TO MEASURE ELASTICITY ?
To generate an elasticTo generate an elastic
Shear vaweShear vawe
To measure its spead VsTo measure its spead Vs
ElasticityElasticity
E E V VSS22
2.5 cm
4 cm
1 cm
Volume of exploration
Volume of exploration > 3 cmVolume of exploration > 3 cm33
Probe position
Probe
PATIENTS WITH HCV CHRONIC HEPATITISPATIENTS WITH HCV CHRONIC HEPATITIS
327 HCV + patients
with 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 biopsy
126 patients
Large biopsy
125 patients
BOX PLOTS. N=251BOX PLOTS. N=251
F01 F2 F3 F410
0
101
102
Ela
stic
ity (
kP
a)
Fibrosis stage0-1 2 3 4
100
1
10
Fibrosis stage (METAVIR)
median IQR
maximum
minimum
Legend
Sti
ffn
ess (
kP
a)
(log
ari
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 1.0
1-Specificité
Sen
sib
ilit
é
F01 / F234
F012 / F34
F0123 / F4
AUROCAUROC
( CONFIDENCE ( CONFIDENCE INTERVALS 95%)INTERVALS 95%)
- - F≥2 : 0.79 (0.73-0.84)F≥2 : 0.79 (0.73-0.84)
- F≥3 : 0.91 (0.87-0.96)- F≥3 : 0.91 (0.87-0.96)
- F=4 : 0.97 (0.93-1.00)- F=4 : 0.97 (0.93-1.00)
F≥2
F≥3
F=4
ROC CURVESROC CURVES
UNI AND MULTIVARIATE ANALYSISUNI AND MULTIVARIATE ANALYSIS
Univariate analysisUnivariate analysis (Kendall’s coefficient)(Kendall’s coefficient)
FibrosisFibrosis Activity Activity Steatosis Steatosis
StiffnessStiffness rr 0.550.55 0.210.21 0.19 0.19pp <0.0001<0.0001 0.00030.0003 0.0008 0.0008
FibrosisFibrosis rr -- 0.360.36 0.17 0.17pp -- <0.0001<0.0001 0.008 0.008
Multivariate analysisMultivariate analysis (multiple regression)(multiple regression)
Only fibrosisOnly fibrosis was significantly correlated to liver stiffness measurement.was significantly correlated to liver stiffness measurement.
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1
1 - Specificity
Se
ns
itiv
ity
F01 versus F234
F012 versus F34
F0123 versus F4
VALIDATION OF DIAGNOSIS ACCURACY IN AN INDEPENDENT HCV POPULATION
Total number of included patients: 639 Number of unreliable liver samples: 86 (13%) Number of unreliable LSM: 59 (9%) Patients kept for statistical analysis : 494
METAVIRMETAVIR
FF 00 11 22 33 44
%% 66 3939 3131 1010 1144
AA 00 11 22 33%% 66 5656 3535 33
SteatosisSteatosisSS 00
1-1-1010
11-11-3030
31-31-100100
%%4477
2727 1515 1010
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)
- Results- Results
- 103 Patients- 103 PatientsCauses : Causes : 71 VHC71 VHC
14 VHB14 VHB
15 VHC+HIV15 VHC+HIV
2 VHB+HIV2 VHB+HIV
1 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 :
CUT-OFF VALUESCUT-OFF VALUES**
ThresholdThreshold SensitivitySensitivity SpecificitySpecificity LRLR
(kPa)(kPa)
F F 2 2 8.78.7 0.550.55 0.840.84 3.53.5
F F 3 3 9.69.6 0.840.84 0.850.85 5.75.7
F = 4F = 4 14.514.5 0.840.84 0.940.94 13.013.0
* Obtained by the jack-knife method.* Obtained by the jack-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.
FIBROSIS AREA FIBROSIS AREA (morphometry)(morphometry)
69 patients with chronic hepatitis C69 patients with chronic hepatitis Cwithout ascites, and previous anti-viral treatmentwithout ascites, and previous anti-viral treatment
- Patients- Patients
F1 F2 F3 F420 21 5 23
- Results- Results
Parameters rFibrosis area METAVIR score 0.66Elasticity METAVIR score 0.65Elasticity fibrosis area 0.74
Spearman correlation testSpearman correlation test
pp < 0.001 < 0.001
Liver elasticity is closely correlated to fibrosis area.
0
10
20
30
40
50
60
70
F1 F2 F3 F4Fibrosis Stage
Ela
sti
cit
é (
kP
a)
0
5
10
15
20
25
Air
e d
e f
ibro
se
(%
)
Elasticité
Aire de fibrose
METAVIRMETAVIR
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
Ela
stic
ité
(kP
a)
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
PROPOSED COMBINATION OF NON PROPOSED COMBINATION OF NON INVASIVE METHODSINVASIVE METHODS
FibroScan + FibroTest
ConcordanceDiscordance
Fibrose minime(FS < 7.1 kPa
+ FT < F2)
Fibrose modérée(FS 7.1 kPa
+ FT F2)
Fibrose sévère(FS 9.5 kPa
+ FT F3)Biopsy
Follow-up TreatmentTreatment
HCC screening Follow-uptreatment
Castera et Al. Gastroenterlogy 2005
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
Se
ns
itiv
ity
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 PROS AND CONSFIBROSCAN PROS AND CONS PROPRO
-easy, quick, not too costy
- very specific for extensive fibrosis or cirrhosis
- Allows to split patients between 3 groups
. Without significant fibrosis
. With extensive fibrosis or cirrhosis
. Intermediate
- closely related to the area of fibrosis in patients with chronic hepatitis
CONCON- high rate of failure in obese patients
- doesn’t take in account liver architecture- disturbed in acute conditions
SCREENING IN HIGH RISK PATIENTSSCREENING IN HIGH RISK PATIENTS
41
34
33
LSM
Blood tests
Confirmation of cirrhosis
LB
LSM>13 kPaoui
Absence of cirrhosis
Suspectedcirrhosis
non
227 patients in alcoholic abstinence program
BEFORE BEFORE TREATMENTTREATMENT
END OF END OF TREATMENTTREATMENT
6 MONTHS 6 MONTHS AFTERAFTER
All (n=85)All (n=85) 14.1 14.1 ± 7.2± 7.2 10.9 10.9 ± 6.5± 6.5 11.2 11.2 ± 8.6± 8.6
SVRSVR 12.0 12.0 ± 6.7± 6.7 9.1 9.1 ± 3.7± 3.7 7.5 7.5 ± 2.4± 2.4
RRRR 14.6 14.6 ± 5.6± 5.6 11.5 11.5 ± 5.0± 5.0 12.8 12.8 ± 7.2± 7.2
NRNR 16.9 16.9 ± 8.1± 8.1 13.3 13.3 ± 9.1± 9.1 16.1 16.1 ± 12.2± 12.2
FOLLOW-UP OF LSM IN TREATED PATIENTS WITH CHRONIC HEPATITIS C
CONCLUSIONCONCLUSION
1) Liver biopsy has been partly challenged by non 1) Liver biopsy has been partly challenged by non invasive methods for assessment of liver fibrosisinvasive methods for assessment of liver fibrosis
2) Non invasive methods have their own limitations : 2) Non invasive methods have their own limitations : 2 might be better than one2 might be better than one
3) Fibroscan could become a useful tool for 3) Fibroscan could become a useful tool for assessing fibrosis variationsassessing fibrosis variations