Transcript Beaugrand - International conference on the management of

Michel BEAUGRAND
EVALUATION OF LIVER FIBROSIS
BLOOD TESTS, LIVER BIOPSY AND
FIBROSCAN
M. Beaugrand
Service d’Hépatologie
Hopital J. Verdier
BONDY 93143
et Université Paris XIII
PHC JANUARY 07
EVALUATION OF FIBROSIS : WHY ?
Fibrosis
Distorted
architecture
Portal
hypertension
Causal agent
FIBROSIS
Chronic liver
Disease
Liver failure
Carcinogenesis
Cirrhosis
Decompensation
2 % to 5 % per year
Hepatocellular
carcinoma
2 % to 5 % per year
Death
4 % per year
ASSESSMENT OF FIBROSIS : WHY ?
Management of individual patients
•
•
Significant fibrosis
Cirrhosis
Treatment
Screening for varices and HCC
Evaluation of treatments
•
Antiviral and antifibrotic drugs
Screening for cirrhosis or extensive fibrosis
•
In high risk patients
EVALUATION OF FIBROSIS : HOW ?
- Liver biopsy
- Blood tests
• Genuine serum markers of fibrosis :
by products of extracellular matrix
metabolism.
• Probabilistic indexes = surrogate markers.
- Fibroscan ( transcient elastography)
LIVER BIOPSY : LIMITATIONS
•
Acceptability
- patients are often reluctant
- even some doctors are reluctant
• Cost
• Morbidity
• Reliability
- liver sample size ideally ≥ 25 mm
- pathologist’s experience
- suboptimal reproductibility of scoring systems
- quantitative assessment unpractical
LENGH OF LIVER BIOPSY
Biopsy length
Bedossa et al, Hepatology 2003
LIVER BIOPSY : PROS AND CONS
PRO
. Not influenced by extrahepatic conditions
. Allows analysis of elementary lesions and comobidities
. May allow assessment of fibrogenesis (molecular
biology)
CON
. Sampling error
. Dependant of pathologist’s experience
. Unavalaible in large parts of the world
BLOOD TESTS
Matrix related
PIIINP, collagen type IV, laminin
Hyaluronic acid, MMP, TIMP
Non maxtrix related
AST, ALT, gamma GT
Bilirubin, prothrombine, platelets
Gammaglobulins, ferritin
Alpha 2 macroglobulin, haptoglobin
Apo A1, cholesterol, HOMA
BLOOD TESTS
Poynard, 1991
Bonacini, 1997
Imbert-Bismut, 2001
Luo, 2002
Forns, 2002
Kaul, 2002
Wai, 2003
Sud, 2004
Lainé, 2004
Rosenberg, 2004
Patel, 2004
Leroy, 2004
Hui, 2005
Lok, 2005
Adams, 2005
Cales, 2005
Prothrombine, GGT, Apo A1
AST/ALAT, platelets, prothrombine
bili, GGT, hapto., a2MG, apoA1
glob/alb, platelets, AST/ALT
age, GGT, cholesterol, platelets
sex, ang.spider angiomas, AST, platelets
AST/platelets
age, AST, cholesterol, HOMA, alcohol
hyaluronate, transferin
age, hyalur., col IV, col VI, laminin, PIIINP, TIMP-1
TIMP-1, a2MG, hyaluronate
PIIIMP, MMP1
BMI, platelets, albumin, bilirubin
AST/ALT, platelets, INR
bili, GGT, hyaluronate, a2MG, age, sex
AST, platelets, prothrombine, hyaluronate,
urea, age
PGA
Fibrotest
APRI
ELF
Fibrospect
Hepascore
Fibrometre
BLOOD TESTS
Fibrotest ®
VHC (n= 339)
index
Imbert-Bismut et al. Lancet 2001;357:2069-75
Metavir
BLOOD TESTS
Fibrotest ®
HCV (n=339)
Métavir ≥ F2
AUC = 0,827
Index < 0,10
Index > 0,60
NPV 100%
PPV > 90%
Liver Biopsy: - 46%
Imbert-Bismut et al. Lancet 2001;357:2069-75
BLOOD TESTS
HCV : F0-1 vs F2-3-4
Ref.
Imbert-Bismut, 2001
Test
Fibrotest
Forns, 2002
AUC
Construction
Validation
0.83
0.85
0.86
0.81
0.88
Wai, 2003
APRI
0.80
Patel, 2004
Fibrospect
0.83
Rosenberg, 2004
ELF
0.78
Leroy, 2004
0.82
Sud, 2004
0.84
Adams, 2005
Hepascore
0.85
0.82
BLOOD TESTS
HCV : F0-1-2-3 vs F4 (cirrhosis)
Ref.
Test
AUC
Construction
Kaul, 2002
Validation
0.94
Wai, 2003
APRI
0.89
Rosenberg, 2004
ELF
0.89
Le Calvez, 2004
Fibrotest
0.92
Adams, 2005
Hepascore
0.94
0.89
0.78
0.81
Lok, 2005
0.94
BLOOD TESTS : PROS AND CONS
PRO
. Easy, non invasive,not too costy
. Allow to split patients in 3 groups
- those without significant fibrosis
- those with extensive fibrosis or cirrhosis
- intermediate
CON
. Studied mainly in naive patients with HCV chronic hepatitis
. External validation lacking (except fibrotest)
. Require standardisation of biochemical methods
. Poorer performances in HBV patients or coinfected HCV-HIV
. Possible influence of extrahepatic conditions
. No international consensus
ELASTOMETRY (FIBROSCAN)
LB x 100
2.5 cm
Volume
1 cm 
Probe
4 cm
Sandrin et al. Ultrasound Med Biol 2003;29:1-8
HOW TO MEASURE ELASTICITY ?
To generate an elastic
Shear vawe
To measure its spead Vs
Elasticity
E  VS2
Volume of exploration > 3 cm3
Probe position
Volume of exploration
2.5 cm
Probe
1 cm 
4 cm
PATIENTS WITH HCV CHRONIC HEPATITIS
327 HCV + patients
with no ascites
23 patients excluded:
unreliable stiffness measurement:
success rate less than 60% upon
10 measurements
53 patients excluded
biopsy not suitable for fibrosis
stage assessment: less than 10
portal tracts in the absence of
cirrhosis
251 patients
included
Small biopsy
126 patients
Large biopsy
125 patients
BOX PLOTS. N=251
10
100
Elasticity (kPa)
Stiffness (kPa)
(logarithmic scale)
2
Legend
maximum
10
10
1
median
minimum
0
10
1
F01
0-1
F2
F3
Fibrosis stage
2
3
Fibrosis stage (METAVIR)
F4
4
IQR
ROC CURVES
AUROC
( CONFIDENCE
INTERVALS 95%)
1.0
Sensibilité
0.8
0.6
- F≥2 : 0.79 (0.73-0.84)
F01 / F234
F≥2
0.4
F012 / F34
F≥3
- F≥3 : 0.91 (0.87-0.96)
- F=4 : 0.97 (0.93-1.00)
F=4
F0123 / F4
0.2
0.0
0.0
0.2
0.4
0.6
1-Specificité
0.8
1.0
UNI AND MULTIVARIATE ANALYSIS
 Univariate analysis (Kendall’s coefficient)
Stiffness
r
p
Fibrosis
0.55
<0.0001
Fibrosis
r
p
-
Activity
0.21
0.0003
Steatosis
0.19
0.0008
0.36
<0.0001
0.17
0.008
 Multivariate analysis (multiple regression)
Only fibrosis was significantly correlated to liver stiffness
measurement.
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
0
1
2
3
%
6
39
31
10
A
%
0
6
S
0
Steatosis
%
4
7
1
56
110
2
35
1130
3
3
31100
27
15
10
4
1
4
1
0.8
Sensitivity
METAVIR
F
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)
0.6
0.4
F01 versus F234
F012 versus F34
F0123 versus F4
Univariate Spearman correlation
METAVIR F: 0.70 (p << 0.001)
METAVIR A: 0.45 (p << 0.001)
Steatosis: 0.35 (p << 0.001)
0.2
0
0
0.2
0.4
0.6
1 - Specificity
0.8
1
LIVER BIOPSIES > 30 mm
- 103 Patients
Causes :
- Results
AUROC
Fibrosis Score :
71 VHC
14 VHB
15 VHC+HIV
2 VHB+HIV
1 VHC+VHB
N
F0 F1 F2 F3 F4
9 58 14 7 15
 F2
 F3
= F4
0.94
0.95
0.93
CUT-OFF VALUES*
The optimum thresholds were chosen to maximize the
sum of sensitivity and specificity.
Threshold
(kPa)
F2
8.7
F3
9.6
F=4
14.5
Sensitivity Specificity LR
* Obtained by the jack-knife method.
0.55
0.84
0.84
0.84
0.85
0.94
3.5
5.7
13.0
FIBROSIS AREA (morphometry)
- Patients
69 patients with chronic hepatitis C
without ascites, and previous anti-viral treatment
METAVIR
- Results
F1
20
F2
21
F4
23
25
60
Elasticité
50
20
Aire de fibrose
40
15
30
10
20
5
10
0
0
F1
F2
F3
F4
Aire de fibrose (%)
Elasticité (kPa)
70
F3
5
Spearman correlation test
p < 0.001
Parameters
Fibrosis area METAVIR score
Elasticity METAVIR score
Elasticity fibrosis area
Fibrosis Stage
 Liver elasticity is closely correlated to fibrosis area.
r
0.66
0.65
0.74
FIBROSCAN VERSUS BLOOD TESTS
FibroScan
Elasticité (kPa)
100
APRI
FibroTest
1.0
6.0
0.7
4.0
0.3
2.0
10
1
0.0
F1
F2
F3
F4
Fibrosis stage
Score METAVIR de fibrose
F1
F2
F3
F4
Fibrosis stage
Score METAVIR de fibrose
0.0
F1
F2
F3
Fibrosis stage
Score METAVIR de fibrose
Castera Al. Gastroenterology 2005
F4
CONCORDANCE WITH LIVER BIOPSY
• AUROC
F01/F234
APRI
0.78
FibroTest
0.85
FibroScan
0.83
Combinaison
0.88
FibroTest+FibroScan
F012/F34
0.84
0.90
0.90
0.95
F0123/F4
0.83
0.87
0.95
0.95
• Percentage of concording results
F01/F234
FibroTest
80
FibroScan
73
Combinaison
84
FibroTest+FibroScan
F0123/F4
81
83
95
PROPOSED COMBINATION OF NON
INVASIVE METHODS
FibroScan + FibroTest
Concordance
Discordance
Biopsy
Fibrose minime
(FS < 7.1 kPa
+ FT < F2)
Fibrose modérée
(FS  7.1 kPa
+ FT  F2)
Fibrose sévère
(FS  9.5 kPa
+ FT  F3)
Follow-up
treatment
Follow-up
Treatment
Treatment
HCC screening
Castera et Al. Gastroenterlogy 2005
FIBROSCAN IN HBV PATIENTS
202 patients
- 15 non interpretable biopsies
- 14 LSM considered as non reliable
Statistical analysis on 173 patients
1
0.9
0.8
0.7
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)
0.6
Sensitivity
AUROC
0.5
0.4
0.3
F01 versus F234
0.2
F0123 versus F34
F0123 versus F4
0.1
0
0
0.2
0.4
0.6
1 - Specificity
0.8
1
FIBROSCAN PROS AND CONS

PRO
-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

CON
- high rate of failure in obese patients
- doesn’t take in account liver architecture
- disturbed in acute conditions
SCREENING IN HIGH RISK PATIENTS
LSM
227 patients in alcoholic
abstinence program
LSM>13 kPa
oui
Suspected
cirrhosis
41
LB
34
Blood tests
non
Absence of
cirrhosis
Confirmation
of cirrhosis
33
FOLLOW-UP OF LSM IN TREATED PATIENTS WITH
CHRONIC HEPATITIS C
BEFORE
END OF
TREATMENT TREATMENT
6 MONTHS
AFTER
All (n=85)
14.1 ± 7.2
10.9 ± 6.5
11.2 ± 8.6
SVR
12.0 ± 6.7
9.1 ± 3.7
7.5 ± 2.4
RR
14.6 ± 5.6
11.5 ± 5.0
12.8 ± 7.2
NR
16.9 ± 8.1
13.3 ± 9.1
16.1 ± 12.2
CONCLUSION
1) Liver biopsy has been partly challenged by non
invasive methods for assessment of liver fibrosis
2) Non invasive methods have their own limitations :
2 might be better than one
3) Fibroscan could become a useful tool for
assessing fibrosis variations